Iminyl-Radical-Promoted C-C Bond Cleavage/Heck-Like Coupling via Dual Cobaloxime and Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.0c02834

We report herein an unprecedented protocol for radical-olefin coupling of α-imino-oxy acids and alkenes for the synthesis of alkene-containing nitriles via synergistic photoredox and cobaloxime catalysis. With visible-light irradiation, the transformation

Full text of DOI:10.1021/acs.joc.0c02834

pubs.acs.org/joc
Article
Iminyl-Radical-Promoted C−C Bond Cleavage/Heck-Like Coupling
via Dual Cobaloxime and Photoredox Catalysis
Jia-Lin Tu, Wan Tang, Wei Xu, and Feng Liu*
Cite This: J. Org. Chem. 2021, 86, 2929−2940
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report herein an unprecedented protocol for
radical−olefin coupling of α-imino-oxy acids and alkenes for the
synthesis of alkene-containing nitriles via synergistic photoredox
and cobaloxime catalysis. With visible-light irradiation, the
transformation provides a variety of corresponding alkene-
containing nitriles under mild reaction conditions. The C−C
bond cleavage/Heck-like coupling reaction could generate E-
selective coupling products with excellent chemo- and stereo-selectivity. This iminyl-radical-mediated reaction is external-oxidant-
free, exhibits wide functional-group compatibility, and occurs with the extrusion of acetone, H2, and CO2.
transformations. On the other hand, Shi12 and Xiao13a
developed Cu-catalyzed and photoredox-catalyzed reductive
cleavage of cyclobutanone oxime esters and Heck-like coupling
INTRODUCTION
The development of methods for C−C bond formation via
radical-mediated reactions is a longstanding endeavor in organic
■
with alkenes, respectively. Inspired by these reports,8c,11−13 we
wondered whether the dual catalytic system could be harnessed
as a novel radical−olefin coupling strategy to obtain a variety of
nitriles with pendant alkenes by an oxidative iminyl-radical
formation process. Herein, we describe an iminyl-radical-
mediated selective C−C bond cleavage/Heck-like coupling of
α-imino-oxy acids and alkenes via synergistic cobaloxime and
photoredox catalysis (Scheme 1d).
synthesis.1 The Heck-type reaction2 via cobalt-catalyzed
radical−olefin coupling has been acknowledged as a powerful
approach for the synthesis of functionalized alkenes which, in
general, are achieved via the addition/elimination sequence of
organocobalt intermediates.3−8 A series of alkyl radical
precursors, such as alkyl halides,3,4 carboxylic acids,5 alkanes,6
and aldehydes,7 have been used as effective coupling partners.
Of these reports, Oshima and co-workers first described an
intermolecular Heck-type coupling of alkyl halides and styrenes
via cobalt−phosphine catalysis (Scheme 1a).3 Furthermore,
Carreira et al. developed a cobaloxime-catalyzed intramolecular
Heck-type reaction of alkyl iodides with pendant olefins upon
visible-light irradiation (Scheme 1a).4 Carboxylic acids and
alkanes have also been employed as efficient alkyl radical
precursors, via dual cobalt and photoredox catalysis, providing
the olefination9 and Heck-type products5,6 (Scheme 1b). Very
recently, our group reported a radical cyclization of aldehydes
with pendant alkenes via synergistic photoredox, cobaloxime,
and amine catalysis (Scheme 1c).7 Note that powerful
photoredox catalysts are essential for the generation of alkyl
radicals, and external oxidants were not required in these
examples.5−7 In spite of these significant advances, the
development of new cobalt-catalyzed radical−olefin reactions
with different alkyl radical precursors to meet various synthetic
demands is still of great interest.
RESULTS AND DISCUSSION
■
We commenced our study by exploring the radical−olefin
coupling of α-imino-oxy acid 1a and styrene (2a) via synergistic
photoredox and cobaloxime catalysis (Table 1). After extensive
screening of reaction parameters (see Tables S1, S2 in the
Supporting Information for details), we were delighted to find
that with 5 mol % Mes−Acr+ (N-methyl-9-mesityl acridinium
perchlorate) and 10 mol % Co(dmgH) (dmgH2)Cl2 as the
synergistic catalyst system, K3PO4 (20 mol %) as the base
catalyst, and mesitylene (0.1 M) as the solvent, this radical
reaction readily furnished the desired product 3a in 71% yield
(E/Z > 20:1) upon irradiation by household blue LEDs (22 W)
at 35 °C. Notably, the control experiments revealed that the dual
photoredox and cobaloxime catalyst system, light, and base were
all essential for the success of the reaction.
With the merge of cobalt catalysis and photoredox organo-
catalysis, we have recently developed an iminyl-radical-mediated
cyclization method for the synthesis of alkene-containing
dihydropyrroles.8c Note that the photoredox decarboxylation
of α-imino-oxy acids via single-electron oxidation could readily
give iminyl radicals,10,11 especially the seminal works from
Leonori’s group and Studer’s lab,10a−f thus enabling diverse
Received: November 27, 2020
Published: January 22, 2021
https://dx.doi.org/10.1021/acs.joc.0c02834
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 2929−2940
2929

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 1. Co-Catalyzed Radical−Olefin Coupling for C−C Bond Formation
With the optimized reaction conditions in hand, the scope of
the reaction was evaluated. Using styrene (2a) as the model
coupling partner, we first examined the reaction of a variety of α-
imino-oxy acids. As shown in Table 2, the substrates with various
R1, R2, and R3 groups proved to be suitable for the reaction,
affording the expected ring-opening/radical−olefin coupling
products in moderate to good yields (3a−k). The substrates
bearing a range of functional groups such as aromatic
substituents, esters, ethers, and amides on the four-membered
ring were all accommodated well, furnishing the corresponding
alkene-containing nitriles 3a−i with excellent E/Z selectivity.
Note that the reaction could be extended to the coupling of
secondary alkyl radicals with an alkene partner, offering 3j and
3k with excellent stereoselectivity. To demonstrate the synthetic
utility of the reaction, a gram-scale reaction (1 g of 1a) was
conducted. The reaction still proceeded very well, furnishing the
desired product 3a in 62% yield.
well-tolerated, regardless of the electronic nature of the aryl
skeleton, furnishing the desired alkenes with excellent E/Z
selectivity (4a−g). In the examples of 4i and 4k−l, sulfur-
containing heterocycles and alkynes are compatible with the
reaction conditions, and the radical−olefin coupling can be
achieved in acceptable yields. Pleasingly, this protocol could
enable access to complex molecules with natural-product-like
cores (4n−o). However, the β-H elimination of organocobalt-
(III) intermediates is not a regioselective process, and it
provided both the internal and terminal alkenes (4p-a and 4p-
b). Unfortunately, the reaction of unactivated and internal
alkenes failed to give the desired products.
Control experiments were conducted to gain more mecha-
nistic insights into the aforementioned transformation (Scheme
2). In the presence of a radical scavenger, 2,2,6,6-tetramethylpi-
peridin-1-oxyl (TEMPO), only a trace amount of the
corresponding product 3a was produced under standard
reaction conditions. As expected, the TEMPO-adduct 5 was
achieved (Scheme 2, eq 1). On the other hand, we observed that
compound 1l can undergo ring-opening/olefination cascade to
give compound 6 as the product (eq 2).
Next, we went on to apply this strategy to the coupling of α-
imino-oxy acid 1a with a variety of alkenes. As depicted in Table
3, broad generality and functional-group compatibility were
observed. An array of activated alkenes could serve as effective
coupling partners in this photocatalytic reaction (4a−p).
Modulation of the aryl ring with a variety of substituents was
On the basis of our observations and previous reports,3−8
a
proposed mechanism is depicted in Scheme 3. The initial step
2930
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Optimization of Reaction Conditions
b
entry
variation
yield (%)
1
2
3
4
5
6
7
8
No
71
<5
51
48
<5
63
43
53
52
<5
0
K2CO3, Li3PO4, or Na3PO4 instead of K3PO4
K3PO4 (10 mol %) as base
K3PO4 (50 mol %) as base
Ir(ppy)3, Ru(bpy)3Cl2·6H2O, or 4CzIPN instead of Mes−Acr+
Co(dmgH)2PyCl instead of Co(dmgH) (dmgH2)Cl2
Co(dmgH)2(4-CN-Py)Cl instead of Co(dmgH) (dmgH2)Cl2
Co(dmgH)2(4-OMe-Py)Cl instead of Co(dmgH) (dmgH2)Cl2
Co(dmgH)2(4-CF3-Py)Cl instead of Co(dmgH) (dmgH2)Cl2
without K3PO4
9
10
11
without photocatalyst, Co catalyst, or light
a
Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), Mes−Acr+ (5 mol %), Co(dmgH) (dmgH2)Cl2 (10 mol %), and K3PO4 (20 mol %) in
b
mesitylene (2 mL, used without dehydration), 35 °C, household blue LEDs (22 W), 72 h. Isolated yield.
involves single oxidation of the carboxylate derived from α-
imino-oxy acid 1 and base by Mes−Acr+*, generating a carboxyl
radical A1, and subsequently, giving an iminyl radical A2 with
loss of CO2 and acetone, followed by ring-opening to deliver an
alkyl radical B. The reduced photocatalyst Mes−Acr• is single-
electron-oxidized by a CoIII complex to close the photoredox
catalytic cycle, as well as to generate a CoII complex. Meanwhile,
the radical addition of alkyl radical B to alkene 2 occurs to give
the alkyl radical C, which can be captured by the CoII complex to
form an organocobalt (III) complex D. The critical β-H
elimination step readily occurs to furnish the alkene-containing
nitriles 3 or 4 and a CoIII−H intermediate. The reaction of the
CoIII−H complex with a proton leads to H2 extrusion and
completion of the cobalt catalytic cycle.
CONCLUSIONS
■
In summary, we have developed an iminyl-radical-mediated
ring-opening/radical−olefin coupling method for the synthesis
of alkene-containing nitriles via an oxidative decarboxylation
process. With the merge of cobalt catalysis and photoredox
organocatalysis, the reaction is external-oxidant-free and occurs
under mild conditions with extrusion of acetone, H2, and CO2.
This method exhibits wide functional-group compatibility and
enables the synthesis of a range of desired products with
excellent E/Z selectivity.
EXPERIMENTAL SECTION
■
General Information. 1H NMR spectra were recorded on a 400 or
600 MHz (100 or 150 MHz for 13C NMR) Agilent NMR spectrometer
with CDCl3 as the solvent and tetramethylsilane (TMS) as the internal
standard. Chemical shifts were reported in parts per million (ppm, δ
2931
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 2. Substrate Scope of α-Imino-oxy Acids
a
Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), Mes−Acr+ (5 mol %), Co(dmgH) (dmgH2)Cl2 (10 mol %), and K3PO4 (20 mol %) in
mesitylene (2 mL, used without dehydration), 35 °C, household blue LEDs (22 W), 72 h. Isolated yield; E/Z and diastereoselectivity (d.r.) ratios,
as determined by crude H NMR spectroscopy. 1a (1 g, 5.84 mmol).
b
1
scale) downfield from TMS at 0.00 ppm and referenced to CDCl3 at
7.26 ppm (for 1H NMR) or 77.16 ppm (for 13C NMR). High-
resolution mass spectroscopy (HRMS) data of products were collected
using an Agilent 6540 Q-TOF (ESI) mass spectrometer. Fourier-
transform infrared (FT-IR) spectra were recorded on a Varian 1000 FT-
IR, νmax in cm−1. Melting points were measured using SGW X-4B and
values are uncorrected. For details on the light source and the material
of the irradiation vessel, see the Supporting Information. All
commercially available reagents and solvents were used as received
unless otherwise specified. Starting materials α-imino-oxy acids 1 were
prepared according to the literature procedures.10d,f,14,15 The photo-
2-(((3-(4-(tert-Butyl)phenyl)cyclobutylidene)amino)oxy)-2-meth-
ylpropanoic Acid (1c). White solid (1.21 g, 74%); m.p. 175−177 °C;
1H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3
Hz, 2H), 3.65−3.55 (m, 1H), 3.51−3.30 (m, 2H), 3.06 (ddt, J = 16.4,
6.8, 3.5 Hz, 2H), 1.55 (s, 6H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 179.2, 158.0, 149.6, 140.9, 126.2, 125.5, 80.8, 39.8, 39.0,
34.5, 32.5, 31.4, 24.22, 24.17; FT-IR (thin film, KBr): ν (cm−1): 2915,
1721, 1384, 1208, 951, 772; HRMS (ESI) m/z: [M + Na]+ calcd for
C18H25N O3Na, 326.1727; found, 326.1718.
−
catalyst Mes−Acr+ClO4 was purchased. All cobalt catalysts were
prepared according to the literature procedures.5,8b,16
2-Methyl-2-(((3-phenylcyclobutylidene)amino)oxy)propanoic
Acid (1b). White solid (870 mg, 88%); m.p. 90−93 °C; 1H NMR (400
MHz, CDCl3): δ 7.38−7.31 (m, 2H), 7.29−7.26 (m, 2H), 7.25−7.22
(m, 1H), 3.69−3.57 (m, 1H), 3.51−3.34 (m, 2H), 3.13−3.00 (m, 2H),
1.54 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.9, 158.3, 143.8,
128.6, 126.7, 126.4, 81.0, 39.7, 38.9, 32.9, 24.21, 24.18; FT-IR (thin
film, KBr): ν (cm−1): 2958, 1708, 1495, 1402, 1162, 967, 615; HRMS
(ESI) m/z: [M + Na]+ calcd for C14H17N O3Na, 270.1101; found,
270.1105.
2-(((3-(Ethoxycarbonyl)cyclobutylidene)amino)oxy)-2-methyl-
propanoic Acid (1d). White solid (948 mg, 78%); m.p. 88−90 °C; 1H
NMR (600 MHz, CDCl3): δ 4.18 (q, J = 7.1 Hz, 2H), 3.28−3.11 (m,
5H), 1.51 (s, 3H), 1.50 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H}NMR
(100 MHz, CDCl3): δ 178.2, 173.8, 156.0, 81.0, 61.1, 35.6, 35.1, 31.4,
24.2, 24.0, 14.1; FT-IR (thin film, KBr): ν (cm−1): 2990, 1712, 1445,
1178, 1006, 9316, 878,728; HRMS (ESI) m/z: [M + Na]+ calcd for
C11H17N O5Na, 266.0999; found, 266.0996.
2932
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a b
,
Table 3. Substrate Scope of Alkenes
a
Reaction conditions: 1 (0.20 mmol), 2 (0.40 mmol), Mes−Acr+ (5 mol %), Co(dmgH) (dmgH2)Cl2 (10 mol %), and K3PO4 (20 mol %) in
mesitylene (2 mL, used without dehydration), 35 °C, household blue LEDs (22 W), 72 h. Isolated yield; E/Z and diastereoselectivity (d.r.) ratios
determined by crude H NMR spectroscopy. Detected by crude H NMR spectroscopy and HRMS.
b
1
1
1H), 3.34−3.06 (m, 2H), 3.05−2.84 (m, 2H), 1.50 (s, 3H), 1.49 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.3, 154.9, 137.4, 128.6,
128.0, 127.9, 80.9, 71.0, 67.2, 40.2, 39.6, 24.2, 24.1; FT-IR (thin film,
KBr): ν (cm−1): 2990, 1728, 1392, 1354, 1260, 1163, 1002, 914;
HRMS (ESI) m/z: [M + Na]+ calcd for C15H19N O4Na, 300.1206;
found, 300.1204.
2-(((3-(Benzyloxy)cyclobutylidene)amino)oxy)-2-methylpropa-
noic Acid (1e). White solid (1.3 g, 95%); m.p. 97−98 °C; H NMR
(400 MHz, CDCl3): δ 7.44−7.29 (m, 5H), 4.48 (s, 2H), 4.30−4.15 (m,
1
2933
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 2. Control Experiments
Scheme 3. Proposed Mechanism
178.6, 156.3, 149.0, 81.5, 80.8, 58.3, 28.3, 23.9; FT-IR (thin film, KBr):
ν (cm−1): 2977, 1694, 1460, 1166, 1125, 943, 766; HRMS (ESI) m/z:
[M + Na]+ calcd for C12H20N2 O5Na, 295.1264; found, 295.1268.
2-Methyl-2-((oxetan-3-ylideneamino)oxy)propanoic Acid (1f).
1
White solid (369 mg, 72%); m.p. 86−89 °C; H NMR (600 MHz,
CDCl3): δ 5.34−5.27 (m, 4H), 1.52 (s, 6H); 13C{1H}NMR (150 MHz,
CDCl3): δ 178.7, 154.0, 81.4, 79.0, 78.9, 23.9; FT-IR (thin film, KBr): ν
(cm−1): 2991, 1696, 1475, 1364, 977, 739; HRMS (ESI) m/z: [M +
Na]+ calcd for C7H11NO4Na, 196.0580; found, 196.0578.
2-Methyl-2-(((3-methyl-3-phenylcyclobutylidene)amino)oxy)-
propanoic Acid (1h). White solid (814 mg, 78%); m.p. 112−114 °C;
1H NMR (600 MHz, CDCl3): δ 9.94 (s, 1H), 7.35 (t, J = 7.4 Hz, 2H),
7.26−7.20 (m, 3H), 3.37−3.21 (m, 2H), 3.14−3.07 (m, 1H), 2.99 (d, J
= 16.0 Hz, 1H), 1.55 (s, 3H), 1.54 (s, 3H), 1.53 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3): δ 179.7, 156.5, 148.7, 128.5, 126.1, 125.2, 80.7,
44.9, 44.3, 38.0, 30.9, 24.2, 24.1; FT-IR (thin film, KBr): ν (cm−1):
2986, 1716, 1593, 1488, 1168, 971; HRMS (ESI) m/z: [M + Na]+ calcd
for C15H19N O3Na, 284.1257; found, 284.1261.
2-(((1-(tert-Butoxycarbonyl)azetidin-3-ylidene)amino)oxy)-2-
methylpropanoic Acid (1g). White solid (479 mg, 63%); m.p. 145−
148 °C; 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 4.67−4.59 (m,
4H), 1.51 (s, 6H), 1.46 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ
2934
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
The residue was purified by flash column chromatography on silica gel
(petroleum/ethyl acetate = 20:1) to give the product as a white solid
(1.98 g, 86%); 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.1 Hz, 2H),
7.47 (d, J = 8.0 Hz, 2H), 6.78 (dd, J = 17.6, 10.9 Hz, 1H), 5.86 (dd, J =
17.6, 0.8 Hz, 1H), 5.34 (dd, J = 10.9, 0.8 Hz, 1H), 1.39 (s, 12H);
13C{1H} NMR (100 MHz, CDCl3): δ 140.3, 136.9, 135.1, 125.6, 114.9,
83.7, 24.9; 11B NMR (128 MHz, CDCl3): δ 30.90 (s).
2-(((7-(tert-Butoxycarbonyl)-7-azaspiro[3.5]nonan-2-ylidene)-
amino)oxy)-2-methylpropanoic Acid (1i). White solid (1.36 g, 95%);
m.p. 92−93 °C; 1H NMR (400 MHz, CDCl3): δ 3.47−3.24 (m, 4H),
2.70−2.64 (m, 4H), 1.60 (t, J = 5.5 Hz, 4H), 1.50 (s, 6H), 1.45 (s, 9H);
13C{1H} NMR (150 MHz, CDCl3): δ 177.8, 156.9, 154.8, 80.8, 79.6,
4-(3-(5-Phenyl-3,4-dihydro-2H-pyrrol-2-yl)prop-1-en-1-yl) Benzyl
2-(1,3-dioxoisoindolin-2-yl)acetate (2m). In a dry round-bottomed
flask, 2-(1,3-dioxoisoindolin-2-yl) acetic acid (1.25 g, 5 mmol) was
weighed and DMF (25 mL) was added. K2CO3 (1.04 g, 6.5 mmol) and
KI (1.25 g, 6.5 mmol) were then added and stirred. To this stirring
suspension, 4-vinylbenzyl chloride (839 mg, 5.5 mmol) was added and
stirred for 12 h at room temperature. After the reaction was complete,
EtOAc (50 mL) and water (30 mL) were added to the mixture and
extracted and washed three times with water. The organic layer was
collected and dried. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 20:1).
41.8, 41.2, 36.4, 33.3, 28.4, 24.1; FT-IR (thin film, KBr): ν (cm−1):
2980, 1684, 1417, 1363, 1236, 1165, 973, 867; HRMS (ESI) m/z: [M +
H]+ calcd for C17H29N2O5, 341.2071; found, 341.2066.
(E)-2-((Bicyclo[3.2.0]hept-3-en-6-ylideneamino)oxy)-2-methyl-
propanoic Acid (1j). White solid (962 mg, 92%); m.p. 86−87 °C; 1H
NMR (400 MHz, CDCl3): δ 5.86−5.71 (m, 2H), 3.81−3.71 (m, 1H),
3.45−3.36 (m, 1H), 3.09 (dd, J = 17.5, 8.3 Hz, 1H), 2.72−2.60 (m,
3H), 1.48 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.8, 166.1,
132.5, 132.0, 81.0, 46.8, 41.1, 38.5, 37.8, 24.3, 24.0; FT-IR (thin film,
KBr): ν (cm−1): 2918, 1705, 1468, 1180, 1021, 965, 714; HRMS (ESI)
m/z: [M + Na]+ calcd for C11H15N O3Na, 232.0944; found, 232.0930.
1
White solid (75%, 1.94 g); m.p. 105−106 °C; H NMR (400 MHz,
CDCl3): δ 7.94−7.80 (m, 2H), 7.80−7.65 (m, 2H), 7.39 (d, J = 8.1 Hz,
2H), 7.29 (d, J = 8.1 Hz, 2H), 6.70 (dd, J = 17.6, 10.9 Hz, 1H), 5.75 (d, J
= 17.6 Hz, 1H), 5.26 (d, J = 10.9 Hz, 1H), 5.18 (s, 2H), 4.48 (s, 2H);
13C{1H}NMR (100 MHz, CDCl3): δ 167.4, 167.2, 137.9, 136.3, 134.5,
134.3, 132.0, 128.6, 126.5, 123.6, 114.5, 67.3, 39.0; FT-IR (thin film,
KBr): ν (cm−1): 2923, 1849, 1544, 1344, 905; HRMS (ESI) m/z: [M +
Na]+ calcd for C19H15NO4Na, 344.0893; found, 344.0891.
2-((Bicyclo[4.2.0]octan-7-ylideneamino)oxy)-2-methylpropanoic
1
Acid (1k). White solid (983 mg, 76%); m.p. 130−132 °C; H NMR
(400 MHz, CDCl3): δ 10.09 (s, 1H), 7.21−7.09 (m, 4H), 4.02−3.71
(m, 2H), 3.42 (d, J = 17.1 Hz, 0.43H), 3.29 (ddd, J = 17.5, 11.4, 9.0 Hz,
1H), 3.21−3.08 (m, 1.57 H), 2.78−2.53 (m, 1H), 1.45/1.37 (s, 3H),
1.42/1.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.5, 163.4/
161.9, 144.9/144.9, 143.5/143.4, 127.3, 127.2, 127.1, 125.2/125.0,
125.0/124.8, 80.8/80.8, 47.6/47.4, 40.8/39.6, 39.8/39.6, 37.2/35.0,
24.4/24.3, 24.1/23.8; FT-IR (thin film, KBr): ν (cm−1):2918, 1708,
1403, 1364, 1162, 1174, 970, 827; HRMS (ESI) m/z: [M + Na]+ calcd
for C15H17N O3Na, 282.1101; found, 282.1106.
((3aS, 5aR, 8aR, 8bS)-2,2,7,7-Tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-3a-yl)methyl 4-Vinylbenzoate
(2n). 4-Vinylbenzoic acid (20 mmol) was added to a mixture of
diacetonefructose (20 mmol) and DMAP (20 mmol) in CH2Cl2 (0.2
M) at room temperature. N,N′-Diisopropylcarbodiimide (22 mmol)
was then added and stirred overnight. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate =
1
10:1). White solid (89%, 6.9 g); m.p. 111−112 °C; H NMR (600
MHz, CDCl3): δ 8.01 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 6.73
(dd, J = 17.6, 10.9 Hz, 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.37 (d, J = 11.0
Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 4.63 (dd, J = 7.9, 2.6 Hz, 1H), 4.46
(d, J = 2.6 Hz, 1H), 4.31 (d, J = 11.8 Hz, 1H), 4.24 (dd, J = 7.9, 1.1 Hz,
1H), 3.94 (dd, J = 13.0, 1.8 Hz, 1H), 3.78 (d, J = 12.9 Hz, 1H), 1.53 (s,
3H), 1.45 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3): δ 165.6, 142.1, 135.9, 130.0, 129.0, 126.1, 116.6, 109.1,
108.8, 101.7, 265, 25.9, 25.5, 24.0; FT-IR (thin film, KBr): ν
(cm−1):2924, 1721, 1605, 1461, 1376, 1070, 860; HRMS (ESI) m/z:
[M + Na]+ calcd for C21H26 O7Na, 413.1571; found, 413.1576.
(E)-2-Methyl-2-(((2-phenylcyclopentylidene)amino)oxy)-
propanoic Acid (1l). White solid (1.0 g, 62%); m.p. 147−149 °C; 1H
NMR (400 MHz, CDCl3): δ 7.30 (t, J = 7.4 Hz, 2H), 7.25−7.17 (m,
3H), 3.83−3.74 (m, 1H), 2.79−2.69 (m, 1H), 2.66−2.51 (m, 1H),
2.34−2.24 (m, 1H), 2.05−1.73 (m, 3H), 1.48 (s, 3H), 1.45 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 176.8, 170.7, 140.9, 128.5, 127.8,
126.8, 81.2, 49.5, 34.9, 28.7, 24.4, 24.3, 22.7; FT-IR (thin film, KBr): ν
(cm−1): 2917, 1717, 1615, 1520, 1305, 1174, 970, 827; HRMS (ESI)
m/z: [M + Na]+ calcd for C15H19N O3Na, 284.1257; found, 284.1260.
Procedures for the Preparation of Alkenes.
(3R, 8S, 9S, 10R, 13R, 14S, 17R)-10,13-Dimethyl-17-((R)-6-
methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradeca-
hydro-1H-cyclopenta[a]phenanthren-3-yl 4-Vinylbenzoate (2o). 4-
Vinylbenzoic acid (20 mmol) was added to a mixture of cholesterol (20
mmol), DMAP (20 mmol), and N,N′-dicyclohexylcarbodiimide (20
mmol) in CH2Cl2 (0.2 M) at room temperature and then stirred
4,4,5,5-Tetramethyl-2-(4-vinylphenyl)-1,3,2-dioxaborolane (2e).5 4-
Vinylphenyl boronic acid (10 mmol) was added to a mixture of 2,3-
dimethylbutane-2,3-diol (20 mmol) and anhydrous MgSO4 (10 mmol)
in Et2O (0.2 M) at room temperature and stirred for 12 h. Next, the
reaction mixture was filtered and concentrated on a rotary evaporator.
2935
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
overnight. Next, the reaction mixture was filtered, concentrated on a
rotary evaporator, and the residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to
(E)-3-(4-(tert-Butyl)phenyl)-6-phenylhex-5-enenitrile (3c). Follow-
ing the general procedure with 2-(((3-(4-(tert-butyl)phenyl)-
cyclobutylidene)amino)oxy)-2-methyl propanoic acid (65 mg, 0.2
mmol) and styrene (42 mg, 0.4 mmol) and purified using flash
chromatography (petroleum ether/EtOAc = 20:1) gave 33 mg of the
title compound (yellow oil; 54% yield); 1H NMR (600 MHz, CDCl3):
δ 7.38 (d, J = 8.2 Hz, 2H), 7.33−7.27 (m, 4H), 7.24−7.17 (m, 3H), 6.49
(d, J = 15.8 Hz, 1H), 6.15−6.02 (m, 1H), 3.11 (p, J = 6.9 Hz, 1H),
2.73−2.60 (m, 4H), 1.33 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3):
δ 150.3, 138.2, 137.0, 133.1, 128.5, 127.4, 126.7, 126.3, 126.1, 125.8,
118.6, 41.5, 38.4, 34.5, 31.3, 23.9; FT-IR (thin film, KBr): ν (cm−1):
2932, 1605, 1578, 1455, 753; HRMS (ESI) m/z: [M + Na]+ calcd for
C22H25NNa, 326.1879; found, 326.1872.
Ethyl (E)-2-(cyanomethyl)-5-phenylpent-4-enoate (3d). Following
the general procedure with 2-(((3-(ethoxycarbonyl)cyclobutylidene)-
amino)oxy)-2-methyl propanoic acid (53 mg, 0.2 mmol) and styrene
(42 mg, 0.4 mmol) and purified using flash chromatography
(petroleum ether/EtOAc = 20:1) gave 37 mg of the title compound
(yellow oil; 76% yield); 1H NMR (600 MHz, CDCl3): δ 7.36−7.29 (m,
4H), 7.24 (t, J = 7.1 Hz, 1H), 6.52 (d, J = 15.7 Hz, 1H), 6.11−6.03 (m,
1H), 4.26−4.17 (m, 2H), 2.89 (p, J = 6.6 Hz, 1H), 2.74−2.59 (m, 4H),
1.32−1.26 (m, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 171.9,
136.6, 134.2, 128.6, 127.7, 126.2, 124.0, 117.7, 61.5, 41.4, 34.4, 18.6,
14.2; FT-IR (thin film, KBr): ν (cm−1): 2921, 1729, 1493, 1364, 1183,
967, 742; HRMS (ESI) m/z: [M + Na]+ calcd for C15H17N O2Na,
266.1151; found, 266.1144.
(E)-3-(Benzyloxy)-6-phenylhex-5-enenitrile (3e). Following the
general procedure with 2-(((3-(ethoxycarbonyl)cyclobutylidene)-
amino)oxy)-2-methylpropanoic acid (60 mg, 0.2 mmol) and styrene
(42 mg, 0.4 mmol) and purified using flash chromatography
(petroleum ether/EtOAc = 20:1) gave 30 mg of the title compound
(yellow oil; 55% yield); 1H NMR (600 MHz, CDCl3): δ 7.40−7.29 (m,
9H), 7.26−7.22 (m, 1H), 6.52 (d, J = 15.8 Hz, 1H), 6.18−6.11 (m,
1H), 4.66 (s, 2H), 3.87−3.80 (m, 1H), 2.67−2.54 (m, 4H); 13C{1H}
NMR (150 MHz, CDCl3): δ 137.4, 136.9, 134.0, 128.6, 128.5, 128.0,
127.8, 127.5, 126.2, 123.8, 117.4, 74.2, 71.8, 37.3, 22.7; FT-IR (thin
film, KBr): ν (cm−1): 2926, 1596, 1501, 1454, 1260, 753; HRMS (ESI)
m/z: [M + Na]+ calcd for C19H19NONa, 300.1359; found, 300.1350.
2-(Cinnamyloxy)acetonitrile (3f). Following the general procedure
with 2-methyl-2-((oxetan-3-ylideneamino)oxy)propanoic acid (40 mg,
0.2 mmol) and styrene (42 mg, 0.4 mmol) and purified using flash
chromatography (petroleum ether/EtOAc = 20:1) gave 25 mg of the
title compound (yellow oil; 72% yield); 1H NMR (600 MHz, CDCl3):
δ 7.41 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.3 Hz,
1H), 6.70 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9, 6.4 Hz, 1H), 4.31 (dd,
J = 6.4, 0.9 Hz, 2H), 4.29 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ
135.9, 135.3, 128.7, 128.3, 126.7, 123.0, 116.0, 71.7, 54.6; FT-IR (thin
film, KBr): ν (cm−1): 2934, 1696, 1475, 1364, 1224, 1047, 977, 739;
HRMS (ESI) m/z: [M + H]+ calcd for C11H12NO, 174.0913; found,
174.0910.
1
give a white solid (88%, 5.66 g). m.p. 172−173 °C; H NMR (400
MHz, CDCl3): δ 7.99 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.75
(dd, J = 17.6, 10.9 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 4.0
Hz, 1H), 5.37 (d, J = 10.9 Hz, 1H), 4.99−4.76 (m, 1H), 2.46 (d, J = 7.7
Hz, 2H), 2.09−1.95 (m, 3H), 1.94−1.66 (m, 3H), 1.65−1.43 (m, 8H),
1.35 (ddd, J = 19.9, 15.5, 8.0 Hz, 4H), 1.26−1.12 (m, 5H), 1.07 (s, 3H),
0.99 (dd, J = 10.5, 5.8 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.87 (dd, J =
6.6, 1.6 Hz, 6H), 0.69 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ
165.7, 141.7, 139.6, 136.1, 130.0, 129.8, 126.0, 122.7, 116.3, 74.5, 56.7,
56.1, 50.0, 42.3, 39.7, 39.5, 38.2, 37.0, 36.6, 36.2, 35.8, 31.9, 31.9, 28.2,
28.0, 27.9, 24.3, 23.8, 22.8, 22.5, 21.0, 19.4, 18.7, 11.8; FT-IR (thin film,
KBr): ν (cm−1):2879, 1710, 1615, 1468, 1274, 1120, 856; HRMS (ESI)
m/z: [M + Na]+ calcd for C36H52 O2Na, 539.3860; found, 539.3857.
General Procedure for the Synthesis of Alkene-Containing
Nitriles. To a 10 mL oven-dried round-bottomed Schlenk bottle
equipped with a magnetic stir bar, the corresponding oxime acid (0.2
mmol, 1.0 equiv.), olefin (0.24 mmol, 1.2 equiv., if solid), Mes−
−
Acr+ClO4 (4.2 mg, 0.01 mmol, 5 mol %), Co(dmgH) (dmgH2)Cl2
(7.2 mg, 0.02 mmol, 10 mol %), and K3PO4 (8.4 mg, 0.04 mmol, 20 mol
%) were added. The corresponding olefin (0.4 mmol, 2.0 equiv., if
liquid) and mesitylene (2 mL) were then added under an argon
atmosphere. The resulting mixture was sealed and then subjected to the
freeze−pump−thaw cycle three times. After that, the reaction mixture
was placed under a 22 W blue LED and irradiated for 72 h. The
temperature was maintained at 35 °C when the LED light was on. After
the reaction was complete (monitored by TLC), the solvent was
removed under reduced pressure and the residue was purified by flash
column chromatography on silica gel.
Gram-Scale Synthesis of Compound 3a. To a 100 mL oven-
dried round-bottomed Schlenk bottle equipped with a magnetic stir
−
bar, 1a (1 g, 5.84 mmol, 1.0 equiv.), Mes−Acr+ClO4 (122 mg, 0.29
mmol, 5 mol %), Co(dmgH) (dmgH2)Cl2 (209 mg, 0.58 mmol, 10 mol
%), and K3PO4 (246 mg, 1.16 mmol, 20 mol %) were added. Styrene
(11.6 mmol, 2.0 equiv.) and mesitylene (40 mL) were then added
under an argon atmosphere. The resulting mixture was sealed and then
subjected to the freeze−pump−thaw cycle three times. After that, the
reaction was placed under a 22 W blue LED and irradiated for 96 h. The
temperature was maintained at 35 °C when the LED light was on. After
the reaction was complete (monitored by TLC), the solvent was
removed under reduced pressure, and the residue was purified by flash
column chromatography on silica to give the desired product 3a in 62%
yield (0.62 g).
(E)-6-Phenylhex-5-enenitrile (3a). Following the general procedure
with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34 mg,
0.2 mmol) and styrene (42 mg, 0.4 mmol) and purified using flash
chromatography (petroleum ether/EtOAc = 20:1) gave 24 mg of the
title compound (yellow oil; 71% yield); 1H NMR (600 MHz, CDCl3):
δ 7.36 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.2 Hz,
1H), 6.47 (d, J = 15.8 Hz, 1H), 6.14 (dt, J = 15.7, 7.1 Hz, 1H), 2.43−
2.34 (m, 4H), 1.85 (p, J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz,
CDCl3): δ 137.1, 132.0, 128.6, 127.6, 127.3, 126.0, 119.5, 31.6, 25.0,
16.4; FT-IR (thin film, KBr): ν (cm−1): 2918, 1652, 1541, 1308, 1457,
743; HRMS (ESI) m/z: [M + H]+ calcd for C12H14N, 172.1121; found,
172.1122.
tert-Butyl cinnamyl(cyanomethyl)carbamate (3g). Following the
general procedure with 2-methyl-2-((oxetan-3-ylideneamino)oxy)-
propanoic acid (54 mg, 0.2 mmol) and styrene (42 mg, 0.4 mmol)
and purified using flash chromatography (petroleum ether/EtOAc =
1
20:1) gave 34 mg of the title compound (yellow oil; 63% yield); H
NMR (600 MHz, CDCl3): δ 7.37 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz,
2H), 7.25 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 15.4 Hz, 1H), 6.16−6.04 (m,
1H), 4.22−4.03 (m, 4H), 1.50 (s, 9H); 13C{1H} NMR (150 MHz,
CDCl3): δ 156.0, 136.0, 128.6, 128.1, 126.5, 123.2, 115.9, 81.0, 49.2,
34.4, 28.2; FT-IR (thin film, KBr): ν (cm−1): 2977, 1698, 1398, 1366,
1244, 1158, 966, 745; HRMS (ESI) m/z: [M + Na]+ calcd for
C16H20N2 O2Na, 295.1417; found, 295.1421.
(E)-3-Methyl-3,6-diphenylhex-5-enenitrile (3h). Following the
general procedure with 2-methyl-2-(((3-methyl-3-
phenylcyclobutylidene)amino)oxy)propanoic acid (57 mg, 0.2
mmol) and styrene (42 mg, 0.4 mmol) and purified using flash
chromatography (petroleum ether/EtOAc = 20:1) gave 29 mg of the
title compound (yellow oil; 56% yield); 1H NMR (600 MHz, CDCl3):
δ 7.40−7.32 (m, 5H), 7.32−7.27 (m, 3H), 7.24−7.19 (m, 2H), 6.46 (d,
J = 15.7 Hz, 1H), 5.85 (dt, J = 15.2, 7.4 Hz, 1H), 2.76−2.71 (m, 1H),
(E)-3,6-Diphenylhex-5-enenitrile (3b). Following the general
procedure with 2-methyl-2-(((3-phenylcyclobutylidene)amino)oxy)-
propanoic acid (49 mg, 0.2 mmol) and styrene (42 mg, 0.4 mmol) and
purified using flash chromatography (petroleum ether/EtOAc = 20:1)
1
gave 31 mg of the title compound (yellow oil; 62% yield); H NMR
(600 MHz, CDCl3): δ 7.37 (t, J = 7.6 Hz, 2H), 7.32−7.28 (m, 6H),
7.27−7.25 (m, 1H), 7.24−7.18 (m, 1H), 6.48 (d, J = 15.8 Hz, 1H),
6.11−6.01 (m, 1H), 3.13 (p, J = 7.1 Hz, 1H), 2.75−2.65 (m, 4H);
13C{1H} NMR (150 MHz, CDCl3): δ 141.2, 136.9, 133.2, 128.9, 128.5,
127.5, 127.4, 127.1, 126.1, 126.0, 118.4, 42.1, 38.4, 23.9; FT-IR (thin
film, KBr): ν (cm−1):2929, 1598, 1575, 1455, 752; HRMS (ESI) m/z:
[M + Na]+ calcd for C18H17NNa, 270.1253; found, 270.1249.
2936
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2.70 (s, 2H), 2.68−2.63 (m, 1H), 1.55 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3): δ 144.0, 137.0, 134.0, 128.7, 128.5, 127.4, 127.0, 126.1,
125.6, 124.7, 118.1, 49.4, 45.1, 30.2, 25.7; FT-IR (thin film, KBr): ν
(cm−1): 2924, 1494, 1443, 968, 746, 695; HRMS (ESI) m/z: [M + H]+
calcd for C19H20N, 262.1590; found, 262.1599.
119.3, 31.7, 24.8, 16.5; 19F NMR (377 MHz, CDCl3): δ −62.50 (s, 3F);
FT-IR (thin film, KBr): ν (cm−1):2925, 1614, 1332, 1162, 1065, 968;
HRMS (ESI) m/z: [M + Na]+ calcd for C13H12F3NNa, 262.0814;
found, 262.0810.
(E)-6-(4-Methoxyphenyl)hex-5-enenitrile (4c). Following the gen-
eral procedure with 2-((cyclobutylideneamino)oxy)-2-methylpropa-
noic acid (34 mg, 0.2 mmol) and 1-methoxy-4-vinylbenzene (54 mg,
0.4 mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 26 mg of the title compound (yellow oil; 65%
yield); 1H NMR (600 MHz, CDCl3): δ 7.33−7.25 (m, 2H), 6.85 (d, J =
8.6 Hz, 2H), 6.40 (d, J = 15.8 Hz, 1H), 5.98 (dt, J = 15.7, 7.0 Hz, 1H),
3.81 (s, 3H), 2.42−2.28 (m, 4H), 1.83 (p, J = 7.1 Hz, 2H); 13C{1H}
NMR (150 MHz, CDCl3): δ 159.0, 131.4, 129.9, 127.2, 125.3, 119.6,
114.0, 55.3, 31.6, 25.1, 16.4; FT-IR (thin film, KBr): ν (cm−1): 2927,
1704, 1647, 1273, 1018, 970, 734; HRMS (ESI) m/z: [M + Na]+ calcd
for C13H15NONa, 224.1046; found, 224.1044.
(E)-6-(4-Fluorophenyl)hex-5-enenitrile (4d). Following the general
procedure with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic
acid (34 mg, 0.2 mmol) and 1-fluoro-4-vinylbenzene (48.8 mg, 0.4
mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 25 mg of the title compound (yellow oil; 66%
yield); 1H NMR (600 MHz, CDCl3): δ 7.30 (dd, J = 8.3, 5.6 Hz, 2H),
6.99 (t, J = 8.6 Hz, 2H), 6.42 (d, J = 15.9 Hz, 1H), 6.10−5.97 (m, 1H),
2.42−2.34 (m, 4H), 1.84 (p, J = 7.2 Hz, 2H); 13C{1H} NMR (150
MHz, CDCl3): δ 162.1 (C−F, 1J C−F = 246.5 Hz), 133.2, 130.8, 127.5
(C−F, 3J C−F = 7.9 Hz), 127.3, 119.5, 115.4 (C−F, 2J C−F = 21.6 Hz),
31.6, 25.0, 16.4; 19F NMR (377 MHz, CDCl3): δ −114.85−−114.97
(m, 1F); FT-IR (thin film, KBr): ν (cm−1): 2928, 1721, 1501, 1259,
967, 799; HRMS (ESI) m/z: [M + Na]+ calcd for C12H12FNNa,
212.0846; found, 212.0840.
(E)-6-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
hex-5-enenitrile (4e). Following the general procedure with 2-
((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34 mg, 0.2
mmol) and 4,4,5,5-tetramethyl-2-(4-vinylphenyl)-1,3,2-dioxaborolane
(92 mg, 0.4 mmol) and purified using flash chromatography
(petroleum ether/EtOAc = 20:1) gave 32 mg of the title compound
(yellow oil; 54% yield); 1H NMR (600 MHz, CDCl3): δ 7.75 (d, J = 8.0
Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 15.8 Hz, 1H), 6.20 (dt, J =
15.7, 7.1 Hz, 1H), 2.42−2.36 (m, 4H), 1.85 (p, J = 7.2 Hz, 2H), 1.34 (s,
12H); 13C{1H}NMR (150 MHz, CDCl3): δ 139.7, 135.1, 132.1, 128.7,
125.4, 119.5, 115.4, 83.7, 31.7, 24.9, 24.8, 16.5; 11B NMR (128 MHz,
CDCl3): δ 30.7 (br, 1B); FT-IR (thin film, KBr): ν (cm−1): 2927, 1608,
1515, 1360, 1144, 859; HRMS (ESI) m/z: [M + H]+ calcd for C18H25B
O2N, 298.1973; found, 298.1967.
(E)-6-(3-Bromophenyl)hex-5-enenitrile (4f). Following the general
procedure with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic
acid (34 mg, 0.2 mmol) and 1-bromo-3-vinylbenzene (73 mg, 0.4
mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 32 mg of the title compound (yellow oil; 65%
yield); 1H NMR (600 MHz, CDCl3): δ 7.49 (s, 1H), 7.34 (d, J = 7.9 Hz,
1H), 7.34 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8
Hz, 1H), 6.39 (d, J = 15.8 Hz, 1H), 6.20−6.07 (m, 1H), 2.42−2.35 (m,
4H), 1.84 (p, J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ
139.2, 130.6, 130.2, 130.1, 129.3, 128.9, 124.8, 122.7, 119.4, 31.6, 24.8,
16.5; FT-IR (thin film, KBr): ν (cm−1): 2933, 1590, 1561, 1473, 1422,
1070, 964, 775; HRMS (ESI) m/z: [M + Na]+ calcd for
C12H1279BrNNa, 272.0045; found, 272.0043.
tert-Butyl 4-Cinnamyl-4-(cyanomethyl)piperidine-1-carboxylate
(3i). Following the general procedure with 2-(((7-(tert-butoxycarbon-
yl)-7-azaspiro[3.5]nonan-2-ylidene)amino)oxy)-2-methylpropanoic
acid (68 mg, 0.2 mmol) and styrene (42 mg, 0.4 mmol) and purified
using flash chromatography (petroleum ether/EtOAc = 20:1) gave 45
mg of the title compound (yellow oil; 66% yield); 1H NMR (600 MHz,
CDCl3): δ 7.36 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.24 (t, J =
7.1 Hz, 1H), 6.54 (d, J = 15.7 Hz, 1H), 6.13 (dt, J = 15.6, 7.7 Hz, 1H),
3.51−3.39 (m, 4H), 2.43 (d, J = 7.7 Hz, 2H), 2.38 (s, 2H), 1.62 (d, J =
8.1 Hz, 2H), 1.57 (dd, J = 7.6, 4.2 Hz, 2H), 1.46 (s, 9H); 13C{1H} NMR
(150 MHz, CDCl3): δ 154.7, 136.7, 134.9, 128.6, 127.6, 126.2, 123.1,
117.5, 79.8, 40.0, 35.9, 35.2, 34.1, 28.4, 26.0; FT-IR (thin film, KBr): ν
(cm−1): 2927, 1681, 1417, 1363, 1248, 1151, 963, 751; HRMS (ESI)
m/z: [M + Na]+ calcd for C21H28N2 O2Na, 363.2043; found, 363.2033.
(E)-2-(5-Styrylcyclopent-2-en-1-yl)acetonitrile (3j). Following the
general procedure with (E)-2-((bicyclo[3.2.0]hept-3-en-6-
ylideneamino)oxy)-2-methylpropanoic acid (42 mg, 0.2 mmol) and
styrene (42 mg, 0.4 mmol) and purified using flash chromatography
(petroleum ether/EtOAc = 20:1) gave 19 mg of the title compound
(yellow oil; 46% yield); 1H NMR (600 MHz, CDCl3): δ 7.36 (d, J = 7.7
Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.46 (d, J =
15.7 Hz, 1H), 6.22 (dd, J = 15.7, 8.0 Hz, 1H), 5.95−5.90 (m, 1H),
5.75−5.70 (m, 1H), 2.90−2.83 (m, 1H), 2.77−2.68 (m, 2H), 2.57 (dd,
J = 16.8, 5.2 Hz, 1H), 2.40 (dd, J = 16.8, 7.0 Hz, 1H), 2.38−2.31 (m,
1H); 13C{1H} NMR (150 MHz, CDCl3): δ 136.9, 132.7, 131.9, 130.8,
130.7, 128.6, 127.4, 126.1, 118.6, 48.6, 48.3, 39.4, 21.7; FT-IR (thin
film, KBr): ν (cm−1): 2921, 1599, 1491, 1447, 966, 746; HRMS (ESI)
m/z: [M + Na]+ calcd for C15H15NNa, 232.1097; found, 232.1089.
(E)-2-(2-Styryl-2,3-dihydro-1H-inden-1-yl)acetonitrile (3k). Fol-
lowing the general procedure with (E)-2-((bicyclo[3.2.0]hept-3-en-6-
ylideneamino)oxy)-2-methylpropanoic acid (56.4 mg, 0.2 mmol) and
styrene (42 mg, 0.4 mmol) and purified using flash chromatography
(petroleum ether/EtOAc = 20:1) gave 20 mg of the title compound
(yellow oil; 39% yield); 1H NMR (600 MHz, CDCl3): δ 7.40−7.37 (m,
2H), 7.36−7.34 (m, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.26−7.22 (m, 4H),
6.57 (d, J = 15.8 Hz, 1H), 6.29 (dd, J = 15.7, 8.7 Hz, 1H), 3.28 (dd, J =
14.0, 6.2 Hz, 1H), 3.19 (dd, J = 15.1, 7.3 Hz, 1H), 3.00−2.94 (m, 1H),
2.91 (dd, J = 15.2, 9.1 Hz, 1H), 2.84 (dd, J = 17.0, 5.0 Hz, 1H), 2.68 (dd,
J = 17.0, 6.6 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3): δ 142.3,
142.1, 136.7, 132.0, 130.8, 128.6, 127.8, 127.6, 127.0, 126.2, 124.7,
123.2, 118.4, 50.7, 46.9, 38.3, 20.1; FT-IR (thin film, KBr): ν (cm−1):
2918, 1508, 1403, 1364, 1174, 958, 847; HRMS (ESI) m/z: [M + Na]+
calcd for C19H17NNa, 282.1253; found, 282.1247.
(E)-6-(p-Tolyl)hex-5-enenitrile (4a). Following the general proce-
dure with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34
mg, 0.2 mmol) and 1-methyl-4-vinylbenzene (47 mg, 0.4 mmol) and
purified using flash chromatography (petroleum ether/EtOAc = 20:1)
1
gave 22 mg of the title compound (yellow oil; 58% yield); H NMR
(600 MHz, CDCl3): δ 7.35 (d, J = 7.6 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H),
6.53 (d, J = 15.8 Hz, 1H), 6.25−6.14 (m, 1H), 2.49−2.45 (m, 4H), 2.44
(s, 3H), 1.94 (p, J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ
137.1, 134.3, 131.9, 129.3, 126.5, 126.0, 119.6, 31.6, 25.1, 21.1, 16.4;
FT-IR (thin film, KBr): ν (cm−1): 2919, 1512, 1208, 971, 774; HRMS
(ESI) m/z: [M + Na]+ calcd for C13H15NNa, 208.1097; found,
208.1092.
(E)-6-(2-Chlorophenyl)hex-5-enenitrile (4g). Following the general
procedure with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic
acid (34 mg, 0.2 mmol) and 1-chloro-2-vinylbenzene (55 mg, 0.4
mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 20 mg of the title compound (yellow oil; 49%
yield); 1H NMR (600 MHz, CDCl3): δ 7.49 (d, J = 7.7 Hz, 1H), 7.34
(d, J = 7.9 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H),
6.83 (d, J = 15.8 Hz, 1H), 6.19−6.08 (m, 1H), 2.48−2.38 (m, 4H), 1.88
(p, J = 7.2 Hz, 2H); 13C{1H}NMR (150 MHz, CDCl3): δ 135.2, 132.7,
130.6, 129.6, 128.34, 128.27, 126.8, 126.7, 119.4, 31.8, 24.9, 16.5; FT-
IR (thin film, KBr): ν (cm−1): 2933, 1590, 2562, 1473, 1422, 1010, 994,
775; HRMS (ESI) m/z: [M + Na]+ calcd for C12H1235ClNNa,
228.0550; found, 228.0544.
(E)-6-(4-(Trifluoromethyl)phenyl)hex-5-enenitrile (4b). Following
the general procedure with 2-((cyclobutylideneamino)oxy)-2-methyl-
propanoic acid (34 mg, 0.2 mmol) and 1-(trifluoromethyl)-4-
vinylbenzene (69 mg, 0.4 mmol) and purified using flash chromatog-
raphy (petroleum ether/EtOAc = 20:1) gave 33 mg of the title
1
compound (yellow oil; 69% yield); H NMR (600 MHz, CDCl3): δ
7.56 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 15.8 Hz,
1H), 6.35−6.14 (m, 1H), 2.47−2.37 (m, 4H), 1.87 (p, J = 7.2 Hz, 2H);
13C{1H} NMR (150 MHz, CDCl3): δ 140.5, 130.8, 130.4, 129.1 (C−F,
2J C−F = 32.4 Hz), 126.2, 125.5, 124.2 (C−F, 1J C−F = 271.7 Hz),
2937
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
6,6-Diphenylhex-5-enenitrile (4h). Following the general procedure
with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34 mg,
0.2 mmol) and ethene-1,1-diyldibenzene (72 mg, 0.4 mmol) and
purified using flash chromatography (petroleum ether/EtOAc = 20:1)
0.24 mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 42 mg of the title compound (yellow solid; m.p.
102−104 °C; 54% yield); 1H NMR (600 MHz, CDCl3): δ 7.89 (dd, J =
5.1, 3.0 Hz, 2H), 7.75 (dd, J = 5.2, 3.0 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H),
7.28 (d, J = 8.1 Hz, 2H), 6.45 (d, J = 15.8 Hz, 1H), 6.20−6.10 (m, 1H),
5.17 (s, 2H), 4.48 (s, 2H), 2.46−2.36 (m, 4H), 1.85 (p, J = 7.2 Hz, 2H);
13C{1H} NMR (150 MHz, CDCl3): δ 167.4, 167.2, 137.4, 134.2, 133.9,
132.0, 131.4, 128.7, 128.4, 126.3, 123.6, 119.4, 67.3, 38.9, 31.6, 24.9,
16.4; FT-IR (thin film, KBr): ν (cm−1): 2927, 1714, 1466, 1412, 1275,
1110, 926, 713; HRMS (ESI) m/z: [M + Na]+ calcd for C23H20N2
O4Na, 411.1315; found, 411.1306.
1
gave 27 mg of the title compound (yellow oil; 55% yield); H NMR
(600 MHz, CDCl3): δ 7.43−7.36 (m, 2H), 7.36−7.31 (m, 1H), 7.30−
7.26 (m, 2H), 7.25−7.21 (m, 3H), 7.16 (d, J = 7.2 Hz, 2H), 6.02 (t, J =
7.4 Hz, 1H), 2.43−2.17 (m, 4H), 1.81 (p, J = 7.3 Hz, 2H); 13C{1H}
NMR (150 MHz, CDCl3): δ 143.8, 142.1, 139.6, 129.7, 128.4, 128.2,
127.23, 127.21, 127.1, 126.6, 119.5, 28.7, 25.7, 16.7; FT-IR (thin film,
KBr): ν (cm−1): 2923, 1523, 1423, 1058, 965, 833; HRMS (ESI) m/z:
[M + Na]+ calcd for C18H17NNa, 270.1253; found, 270.1256.
(E)-6-(4-(Benzo[b]thiophen-2-yl)phenyl)hex-5-enenitrile (4i). Fol-
lowing the general procedure with 2-((cyclobutylideneamino)oxy)-2-
methylpropanoic acid (34 mg, 0.2 mmol) and 2-(4-vinylphenyl)benzo-
[b]thiophene (57 mg, 0.24 mmol) and purified using flash
chromatography (petroleum ether/EtOAc = 20:1) gave 33 mg of the
title compound (yellow solid; m.p. 134−135 °C; 54% yield); 1H NMR
(600 MHz, CDCl3): δ 7.96−7.90 (m, 2H), 7.55 (d, J = 8.0 Hz, 2H),
7.47 (d, J = 8.0 Hz, 2H), 7.44−7.38 (m, 3H), 6.54 (d, J = 15.8 Hz, 1H),
6.28−6.11 (m, 1H), 2.47−2.39 (m, 4H), 1.88 (p, J = 7.1 Hz, 2H);
13C{1H} NMR (150 MHz, CDCl3): δ 140.7, 137.8, 137.7, 136.4, 135.0,
((3aS, 5aR, 8aR, 8bS)-2,2,7,7-Tetramethyltetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-3a-yl)methyl 4-((E)-5-cyano-
pent-1-en-1-yl)benzoate (4n). Following the general procedure with
2-((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34 mg, 0.2
mmol) and ((3aS, 5aR, 8aR, 8bS)-2,2,7,7-tetramethyl tetrahydro-3aH-
bis([1,3]dioxolo)[4,5-b:4′,5′-d]pyran-3a-yl)methyl 4-vinylbenzoate
(94 mg, 0.24 mmol) and purified using flash chromatography
(petroleum ether/EtOAc = 20:1) gave 52 mg of the title compound
1
(yellow solid; m.p. 123−124 °C; 57% yield); H NMR (600 MHz,
CDCl3): δ 8.00 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 6.49 (d, J =
15.9 Hz, 1H), 6.33−6.21 (m, 1H), 4.68 (d, J = 11.8 Hz, 1H), 4.64 (dd, J
= 7.9, 2.4 Hz, 1H), 4.46 (d, J = 2.4 Hz, 1H), 4.31 (d, J = 11.8 Hz, 1H),
4.26 (d, J = 7.9 Hz, 1H), 3.99−3.91 (m, 1H), 3.80 (d, J = 13.0 Hz, 1H),
2.47−2.38 (m, 3H), 1.86 (p, J = 7.2 Hz, 2H), 1.54 (s, 3H), 1.46 (s, 3H),
1.36 (s, 3H), 1.34 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 165.7,
141.7, 131.2, 130.7, 130.1, 129.8, 128.5, 125.9, 119.3, 109.2, 108.8,
101.7, 70.8, 70.5, 70.1, 65.2, 61.3, 31.7, 26.5, 25.9, 25.5, 24.8, 24.0, 16.5;
FT-IR (thin film, KBr): ν (cm−1): 2936, 1719, 1606, 1376, 1251, 1201,
976, 731; HRMS (ESI) m/z: [M + Na]+ calcd for C25H31N O7Na,
480.1993; found, 480.1990.
131.6, 128.9, 128.0, 126.4, 124.4, 124.3, 123.3, 122.94, 122.87, 119.5,
31.7, 25.01, 16.5; FT-IR (thin film, KBr): ν (cm−1): 2923, 1523, 1423,
1058, 965, 833, 731; HRMS (ESI) m/z: [M + Na]+ calcd for
C20H17NNaS, 326.0974; found, 326.0980.
(E)-6-(Naphthalen-2-yl)hex-5-enenitrile (4j). Following the general
procedure with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic
acid (34 mg, 0.2 mmol) and 2-vinylnaphthalene (37 mg, 0.24 mmol)
and purified using flash chromatography (petroleum ether/EtOAc =
20:1) gave 30 mg of the title compound (yellow solid; m.p. 72−73 °C;
68% yield); 1H NMR (600 MHz, CDCl3): δ 7.82−7.76 (m, 3H), 7.69
(s, 1H), 7.57 (dd, J = 8.5, 1.5 Hz, 1H), 7.50−7.41 (m, 2H), 6.63 (d, J =
15.8 Hz, 1H), 6.26 (dt, J = 15.7, 7.0 Hz, 1H), 2.49−2.40 (m, 4H), 1.89
(p, J = 7.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 134.6, 133.7,
132.9, 132.2, 128.2, 128.0, 127.9, 127.7, 126.3, 125.82, 125.78, 123.4,
119.5, 31.8, 25.1, 16.5; FT-IR (thin film, KBr): ν (cm−1): 2920, 1735,
1455, 1125, 1016, 974, 751; HRMS (ESI) m/z: [M + Na]+ calcd for
C16H15NNa, 244.1097; found, 244.1096.
(E)-6-(Benzo[b]thiophen-2-yl)hex-5-enenitrile (4k). Following the
general procedure with 2-((cyclobutylideneamino)oxy)-2-methylpro-
panoic acid (34 mg, 0.2 mmol) and 2-vinylbenzo[b]thiophene (38 mg,
0.24 mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 33 mg of the title compound (yellow solid; m.p.
64−65 °C; 72% yield); 1H NMR (600 MHz, CDCl3): δ 7.77−7.72 (m,
1H), 7.67 (d, J = 7.3 Hz, 1H), 7.33−7.26 (m, 2H), 7.09 (s, 1H), 6.69 (d,
J = 15.6 Hz, 1H), 6.10−6.01 (m, 1H), 2.48−2.36 (m, 4H), 1.86 (p, J =
7.2 Hz, 2H); 13C {1H} NMR (150 MHz, CDCl3): δ 142.2, 140.0, 138.6,
130.2, 125.9, 124.6, 124.4, 123.4, 122.1, 122.0, 119.4, 31.5, 24.8, 16.5;
FT-IR (thin film, KBr): ν (cm−1): 2926, 1514, 1457, 1220, 954, 758;
HRMS (ESI) m/z: [M + Na]+ calcd for C14H13NNaS, 250.0661; found,
250.0659.
(E/Z)-8-Phenyloct-5-en-7-ynenitrile (4l). Following the general
procedure with 2-((cyclobutylideneamino)oxy)-2-methylpropanoic
acid (34 mg, 0.2 mmol) and but-3-en-1-yn-1-ylbenzene (51 mg, 0.4
mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 16 mg of the title compound (yellow oil; 42%
yield); 1H NMR (600 MHz, CDCl3): δ 7.49−7.38 (m, 2H), 7.36−7.27
(m, 3H), 6.15 (dt, J = 14.6, 7.2 Hz, 0.33H), 5.92 (dt, J = 10.7, 7.5 Hz,
0.66H), 5.84−5.75 (m, 1H), 2.56 (q, J = 7.3 Hz, 1H), 2.47−2.30 (m,
3H), 1.89−1.78 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ 141.3/
140.3, 131.4, 128.33, 128.29, 128.2/128.1, 119.5/119.2, 111.9/111.6,
94.5/88.9, 87.5/85.5, 31.7/29.1, 24.8/24.5, 16.6/16.4; FT-IR (thin
film, KBr): ν (cm−1): 2927, 1681, 1418, 1362, 1249, 1096, 961, 733;
HRMS (ESI) m/z: [M + Na]+ calcd for C14H13NNa, 218.0940; found,
218.0934.
(2R, 8S, 9S, 10R, 13R, 14S, 17R)-10,13-Dimethyl-17-((R)-6-
methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradeca-
hydro-1H-cyclopenta[a]phenanthren-2-yl 4-((E)-5-cyanopent-1-en-
1-yl)benzoate (4o). Following the general procedure with 2-
((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34 mg, 0.2
mmol) and (2R, 8S, 9S, 10R, 13R, 14S, 17R)-10,13-dimethyl-17-
((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra-
deca hydro-1H-cyclopenta[a]phenanthren-2-yl 4-vinylbenzoate (124
mg, 0.24 mmol) and purified using flash chromatography (petroleum
ether/EtOAc = 20:1) gave 68 mg of the title compound (yellow solid;
m.p. 164−165 °C; 58% yield); 1H NMR (600 MHz, CDCl3): δ 7.97 (d,
J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 15.8 Hz, 1H),
6.34−6.16 (m, 1H), 5.41 (d, J = 4.0 Hz, 1H), 4.93−4.79 (m, 1H), 2.46
(d, J = 7.8 Hz, 2H), 2.43−2.38 (m, 4H), 2.05−1.96 (m, 3H), 1.94−1.89
(m, 1H), 1.88−1.84 (m, 2H), 1.83 (d, J = 7.8 Hz, 1H), 1.77−1.69 (m,
1H), 1.57 (dd, J = 6.2, 4.0 Hz, 2H), 1.55−1.50 (m, 3H), 1.46 (dd, J =
10.1, 4.6 Hz, 2H), 1.38 (s, 1H), 1.35 (d, J = 4.3 Hz, 2H), 1.29 (s, 1H),
1.22−1.18 (m, 2H), 1.15 (d, J = 3.0 Hz, 2H), 1.13−1.10 (m, 2H), 1.06
(s, 3H), 1.03−0.98 (m, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.6,
3H), 0.86 (d, J = 6.6, 3H), 0.69 (s, 3H); 13C {1H} NMR (150 MHz,
CDCl3): δ 165.7, 141.3, 139.6, 131.3, 130.3, 129.9, 129.5, 125.8, 122.7,
119.3, 74.5, 56.7, 56.1, 50.0, 42.3, 39.7, 39.5, 38.2, 37.0, 36.6, 36.2, 35.8,
31.91, 31.86, 31.7, 28.2, 28.0, 27.9, 24.8, 24.3, 23.8, 22.8, 22.6, 21.0,
19.4, 18.7, 16.5, 11.9; FT-IR (thin film, KBr): ν (cm−1): 2930, 1704,
1606, 1466, 1274, 1109, 970, 760; HRMS (ESI) m/z: [M + Na]+ calcd
for C40H57N O2Na, 606.4282; found, 606.4278.
Benzyl 6-Cyano-2-methylenehexanoate (4p-a). Following the
general procedure with 2-((cyclobutylideneamino)oxy)-2-methylpro-
panoic acid (34 mg, 0.2 mmol) and benzyl methacrylate (53 mg, 0.3
mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 16 mg of the title compound (yellow oil; 32%
yield); 1H NMR (600 MHz, CDCl3): δ 7.40−7.35 (m, 4H), 7.35−7.31
(m, 1H), 6.24 (s, 1H), 5.59 (s, 1H), 5.20 (d, J = 3.8 Hz, 2H), 2.40−2.32
(m, 4H), 1.71−1.62 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3): δ
166.7, 139.6, 135.9, 128.6, 128.2, 128.1, 125.7, 119.5, 66.5, 31.0, 27.5,
24.9, 17.0; FT-IR (thin film, KBr): ν (cm−1): 2918, 1720, 1621, 1364,
1162, 1174, 970, 827; HRMS (ESI) m/z: [M + Na]+ calcd for C15H17N
O2Na, 266.1151; found, 266.1144.
(E)-4-(5-Cyanopent-1-en-1-yl)benzyl 2-(1,3-Dioxoisoindolin-2-
yl)acetate (4m). Following the general procedure with 2-
((cyclobutylideneamino)oxy)-2-methylpropanoic acid (34 mg, 0.2
mmol) and 4-vinylbenzyl 2-(1,3-dioxoisoindolin-2-yl)acetate (77 mg,
2938
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Benzyl (E)-6-cyano-2-methylhex-2-enoate (4p-b). Following the
general procedure with 2-((cyclobutylideneamino)oxy)-2-methylpro-
panoic acid (34 mg, 0.2 mmol) and benzyl methacrylate (53 mg, 0.3
mmol) and purified using flash chromatography (petroleum ether/
EtOAc = 20:1) gave 21 mg of the title compound (yellow oil; 43%
yield); 1H NMR (600 MHz, CDCl3): δ 7.40−7.35 (m, 4H), 7.35−7.31
(m, 1H), 6.72 (t, J = 7.4 Hz, 1H), 5.19 (s, 2H), 2.41−2.33 (m, 4H), 1.90
(s, 3H), 1.82 (p, J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3): δ
167.5, 139.3, 136.1, 129.7, 128.5, 128.1, 128.0, 119.1, 66.4, 27.3, 24.35,
16.7, 12.6; FT-IR (thin film, KBr): ν (cm−1): 2918, 1718, 1580, 1364,
1165, 1174, 970, 827; HRMS (ESI) m/z: [M + Na]+ calcd for C15H17N
O2Na, 266.1151; found, 266.1156.
AUTHOR INFORMATION
■
Corresponding Author
Feng Liu − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China; Key Laboratory of
Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
People’s Republic of China; orcid.org/0000-0003-2669-
5448; Email: fliu2@suda.edu.cn
4-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)butanenitrile (5). Col-
orless oil; 29% yield (13 mg). 1H NMR (600 MHz, CDCl3): δ 3.85 (t, J
= 5.8 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 1.94−1.83 (m, 2H), 1.50−1.29
(m, 6H), 1.16 (s, 6H), 1.10 (s, 6H); 13C{1H}NMR (150 MHz,
CDCl3): δ 119.7, 73.6, 59.8, 39.6, 33.1, 25.1, 20.1, 14.5; HRMS (ESI)
m/z: [M + Na]+ calcd for C13H24N2ONa, 247.1781; found, 247.1775.
(E)-5-Phenylpent-4-enenitrile (6). Yellow oil; 45% yield (14 mg).
1H NMR (600 MHz, CDCl3): δ 7.38−7.35 (m, 2H), 7.34−7.30 (m,
2H), 7.27−7.23 (m, 1H), 6.52 (d, J = 15.8 Hz, 1H), 6.18 (dt, J = 15.8,
6.8 Hz, 1H), 2.57−2.52 (m, 2H), 2.50−2.46 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 136.7, 133.0, 128.7, 127.8, 126.3, 125.6, 119.2,
28.8, 17.6; FT-IR (thin film, KBr): ν (cm−1): 2933, 1590, 1561, 1473,
1422, 1070, 994, 775; HRMS (ESI) m/z: [M + Na]+ calcd for
C11H11NNa, 180.0784; found, 180.0786.
Control Experiment 1 (Scheme 2, eq 1). To a 10 mL oven-dried
round-bottomed Schlenk bottle equipped with a magnetic stir bar, 1a
(34 mg, 0.2 mmol), 2a (42 mg, 0.4 mmol), Mes−Acr+ClO4− (4.2 mg,
0.01 mmol, 5 mol %), Co(dmgH) (dmgH2)Cl2 (7.2 mg, 0.02 mmol, 10
mol %), and K3PO4 (8.4 mg, 0.04 mmol) were added and dissolved in
mesitylene (2 mL). Then, TEMPO (62 mg, 0.4 mmol) was added to
the reaction system. The resulting mixture was sealed and then
subjected to the freeze−pump−thaw cycle three times. After that, the
reaction system was placed under a 22 W blue LED and irradiated for 72
h. The temperature was maintained at 35 °C when the LED light was
on. After the reaction was complete (monitored by TLC), the solvent
was removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel. The crude product was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate 30:1) to give the desired product 5 as an oil in 29% yield (13
mg).
Authors
Jia-Lin Tu − Jiangsu Key Laboratory of Neuropsychiatric
Diseases and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China
Wan Tang − Jiangsu Key Laboratory of Neuropsychiatric
Diseases and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China
Wei Xu − Jiangsu Key Laboratory of Neuropsychiatric Diseases
and Department of Medicinal Chemistry, College of
Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu
215123, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02834
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of the
Jiangsu Higher Education Institutions of China (grant no.
18KJA350001) and the Priority Academic Program Develop-
ment of the Jiangsu Higher Education Institutions (PAPD) is
acknowledged.
Control Experiment 2 (Scheme 2, eq 2). To a 10 mL oven-dried
round-bottomed Schlenk bottle equipped with a magnetic stir bar, (E)-
2-methyl-2-(((2-phenylcyclopentylidene)amino)oxy)propanoic acid
(52 mg, 0.2 mmol), Mes−Acr+ClO4− (4.2 mg, 0.01 mmol, 5 mol %),
Co(dmgH) (dmgH2)Cl2 (7.2 mg, 0.02 mmol, 10 mol %), and
potassium phosphate (8.4 mg, 0.04 mmol, 20 mol %) were added.
Mesitylene (2 mL) was then added under an argon atmosphere. The
resulting mixture was sealed and then subjected to the freeze−pump−
thaw cycle three times. After that, the reaction mixture was placed under
a 22 W blue LED and irradiated for 72 h. The temperature was
maintained at 35 °C when the LED light was on. After the reaction
finished (monitored by TLC), the solvent was removed under reduced
pressure and the residue was purified by flash column chromatography
on silica gel. The crude product was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate, 30:1) to give the desired
product 6 as an oil in 45% yield (14 mg).
REFERENCES
■
(1) Radicals in Organic Synthesis. Renaud, P.; Sibi, M. P., Eds. Wiley-
VCH Verlag GmbH: Weinheim, Germany, 2001.
(2) For examples of Pd-catalyzed alkyl Heck reactions see:
(a) McMahon, C. M.; Alexanian, E. J. Palladium-Catalyzed Heck-
Type Cross-Couplings of Unactivated Alkyl Iodides. Angew. Chem., Int.
Ed. 2014, 53, 5974. (b) Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y.
Irradiation-Induced Heck Reaction of Unactivated Alkyl Halides at
Room Temperature. J. Am. Chem. Soc. 2017, 139, 18307.
(3) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K. Cobalt-
Catalyzed Heck-Type Reaction of Alkyl Halides with Styrenes. J. Am.
Chem. Soc. 2002, 124, 6514.
(4) (a) Weiss, M. E.; Kreis, L. M.; Lauber, A.; Carreira, E. M. Cobalt-
Catalyzed Coupling of Alkyl Iodides with Alkenes: Deprotonation of
Hydridocobalt Enables Turnover. Angew. Chem., Int. Ed. 2011, 50,
11125. (b) Kreis, L. M.; Krautwald, S.; Pfeiffer, N.; Martin, R. E.;
Carreira, E. M. Photocatalytic Synthesis of Allylic Trifluoromethyl
Substituted Styrene Derivatives in Batch and Flow. Org. Lett. 2013, 15,
1634.
(5) Cao, H.; Jiang, H.; Feng, H.; Kwan, J. M. C.; Liu, X.; Wu, J. Photo-
induced Decarboxylative Heck-Type Coupling of Unactivated
Aliphatic Acids and Terminal Alkenes in the Absence of Sacrificial
Hydrogen Acceptors. J. Am. Chem. Soc. 2018, 140, 16360.
(6) Cao, H.; Kuang, Y.; Shi, X.; Wong, K. L.; Tan, B. B.; Kwan, J. M.
C.; Wu, J. Photoinduced site-selective alkenylation of alkanes and
aldehydes with aryl alkenes. Nat. Commun. 2020, 11, 1956.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02834.
Experimental details, including photochemical reaction
setup, optimization of reaction conditions, and determi-
nation of hydrogen gas with GC, and copies of 1H and 13C
NMR spectra for all compounds (PDF)
2939
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(7) Liu, J.-L.; Tu, J.-L.; Liu, F. Visible-Light-Promoted Intramolecular
α-Allylation of Aldehydes in the Absence of Sacrificial Hydrogen
Acceptors. Org. Lett. 2020, 22, 7369.
(16) Du, P.; Schneider, J.; Luo, G.; Brennessel, W. W.; Eisenberg, R.
Visible Light-Driven Hydrogen Production from Aqueous Protons
Catalyzed by Molecular Cobaloxime Catalysts. Inorg. Chem. 2009, 48,
4952.
(8) (a) Zhang, G.; Zhang, L.; Yi, H.; Luo, Y.; Qi, X.; Tung, C.-H.; Wu,
L.-Z.; Lei, A. Visible-light induced oxidant-free oxidative cross-coupling
for constructing allylic sulfones from olefins and sulfinic acids. Chem.
Commun. 2016, 52, 10407. (b) Liu, W.-Q.; Lei, T.; Zhou, S.; Yang, X.-
L.; Li, J.; Chen, B.; Sivaguru, J.; Tung, C.-H.; Wu, L.-Z. Cobaloxime
Catalysis: Selective Synthesis of Alkenylphosphine Oxides under
Visible Light. J. Am. Chem. Soc. 2019, 141, 13941. (c) Tu, J.-L.; Liu,
J.-L.; Tang, W.; Su, M.; Liu, F. Radical Aza-Cyclization of α-Imino-oxy
Acids for Synthesis of Alkene-Containing N-Heterocycles via Dual
Cobaloxime and Photoredox Catalysis. Org. Lett. 2020, 22, 1222.
(9) (a) Sun, X.; Chen, J.; Ritter, T. Catalytic dehydrogenative
decarboxyolefination of carboxylic acids. Nat. Chem. 2018, 10, 1229.
Cartwright, K. C.; Tunge, J. A. Decarboxylative Elimination of N-Acyl
Amino Acids via Photoredox/Cobalt Dual Catalysis. ACS Catal. 2018,
8, 11801.
(10) Examples on decarboxylative nitrogen radical formation, see:
(a) Jiang, H.; Seidler, G.; Studer, A. Carboamination of Unactivated
Alkenes through Three-Component Radical Conjugate Addition.
Angew. Chem., Int. Ed. 2019, 58, 16528. (b) Jiang, H.; Studer, A.
Amidyl Radicals by Oxidation of α-Amido-oxy Acids: Transition-
Metal-Free Amidofluorination of Unactivated Alkenes. Angew. Chem.,
Int. Ed. 2018, 57, 10707. (c) Jiang, H.; Studer, A. Iminyl-Radicals by
Oxidation of α-Imino-oxy Acids: Photoredox-Neutral Alkene Carboi-
mination for the Synthesis of Pyrrolines. Angew. Chem., Int. Ed. 2017,
56, 12273. (d) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.; Sheikh, N.
S.; Leonori, D. Photoinduced Remote Functionalisations by Iminyl
Radical Promoted C−C and C−H Bond Cleavage Cascades. Angew.
Chem., Int. Ed. 2018, 57, 744. (e) Davies, J.; Sheikh, N. S.; Leonori, D.
Photoredox Imino Functionalizations of Olefins. Angew. Chem., Int. Ed.
2017, 56, 13361. (f) Dauncey, E. M.; Dighe, S. U.; Douglas, J. J.;
Leonori, D. A dual photoredox-nickel strategy for remote functionaliza-
tion via iminyl radicals: radical ring-opening-arylation, -vinylation and
-alkylation cascades. Chem. Sci. 2019, 10, 7728. (g) Le Vaillant, F.;
́
Garreau, M.; Nicolai, S.; Grynova, G.; Corminboeuf, C.; Waser, J. Fine-
tuned organic photoredox catalysts for fragmentation-alkynylation
cascades of cyclic oxime ethers. Chem. Sci. 2018, 9, 5883. (h) Cabrera-
Afonso, M. J.; Cembellín, S.; Halima-Salem, A.; Berton, M.; Marzo, L.;
́
Miloudi, A.; Maestro, M. C.; Aleman, J. Metal-free visible light-
promoted synthesis of isothiazoles: a catalytic approach for N−S bond
formation from iminyl radicals under batch and flow conditions. Green
Chem. 2020, 22, 6792.
(11) For a review, see: Jiang, H.; Studer, A. Chemistry with N-
Centered Radicals Generated by Single-Electron Transfer-Oxidation
Using Photoredox Catalysis. CCS Chem. 2019, 1, 38.
(12) Zhao, B.; Shi, Z. Copper-Catalyzed Intermolecular Heck-Like
Coupling of Cyclobutanone Oximes Initiated by Selective C−C Bond
Cleavage. Angew. Chem., Int. Ed. 2017, 56, 12727.
(13) (a) Yu, X. Y.; Chen, J. R.; Wang, P. Z.; Yang, M. N.; Liang, D.;
Xiao, W. J. A Visible-Light-Driven Iminyl Radical-Mediated C−C
Single Bond Cleavage/Radical Addition Cascade of Oxime Esters.
Angew. Chem., Int. Ed. 2018, 57, 738. (b) Lu, B.; Cheng, Y.; Chen, L.-Y.;
Chen, J.-R.; Xiao, W.-J. Photoinduced Copper-Catalyzed Radical
Aminocarbonylation of Cycloketone Oxime Esters. ACS Catal. 2019, 9,
8159. (c) Chen, J.; Wang, P.-Z.; Lu, B.; Liang, D.; Yu, X.-Y.; Xiao, W.-J.;
Chen, J.-R. Enantioselective Radical Ring-Opening Cyanation of
Oxime Esters by Dual Photoredox and Copper Catalysis. Org. Lett.
2019, 21, 9763. (d) Hu, X.-Q.; Liu, Z.-K.; Hou, Y.-X.; Gao, Y. Single
Electron Activation of Aryl Carboxylic Acids. iScience 2020, 23, 101266.
(14) Xu, Y.; Su, T.; Huang, Z.; Dong, G. Practical Direct α-Arylation
of Cyclopentanones by Palladium/Enamine Cooperative Catalysis.
Angew. Chem., Int. Ed. 2016, 55, 2559.
(15) Trost, B. M.; Xie, J. Palladium-catalyzed diastereo- and
enantioselective Wagner-Meerwein shift: control of absolute stereo-
chemistry in the C-C bond migration event. J. Am. Chem. Soc. 2008,
130, 6231.
2940
https://dx.doi.org/10.1021/acs.joc.0c02834
J. Org. Chem. 2021, 86, 2929−2940