Hydrosilane-Mediated Electrochemical Reduction of Amides

Article abstract of DOI:10.1021/acs.joc.1c00931

Electrochemical reduction of amides was achieved by using a hydrosilane without any toxic or expensive metals. The key reactive ketyl radical intermediate was generated by cathodic reduction. Continuous reaction with anodically generated silyl radicals or zinc bromide resulted in chemoselective deoxygenation to give the corresponding amines.

Full text of DOI:10.1021/acs.joc.1c00931

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Hydrosilane-Mediated Electrochemical Reduction of Amides
Kazuhiro Okamoto, Shingo Nagahara, Yasushi Imada, Risako Narita, Yoshikazu Kitano,
and Kazuhiro Chiba*
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ABSTRACT: Electrochemical reduction of amides was achieved by using a hydrosilane without
any toxic or expensive metals. The key reactive ketyl radical intermediate was generated by
cathodic reduction. Continuous reaction with anodically generated silyl radicals or zinc bromide
resulted in chemoselective deoxygenation to give the corresponding amines.
INTRODUCTION
■
Due to the strong resonance of the N−CO moiety, a mild
reduction of amides to amines remains a simple but
challenging synthetic transformation. Lithium aluminum
hydride (LiAlH4) and diborane (B2H6) are commonly used
reductants for this type of transformation despite their
flammability.1 The development of a mild and green
methodology for amide reduction is attractive as a “key
green chemistry research area”; therefore, many researchers
have been making an effort to develop safe methods for amide
reduction.2 For example, the reaction of a zinc hydride species
with amides gives the corresponding amines with high
chemoselectivity.2a,b Samarium iodide (SmI2) generates a
reactive ketyl radical species from amides under mild
conditions but tends to give the corresponding alcohols via
C−N bond scission.2c Lanthanoid-based Lewis acid catalysts
have broad-scope hydrogenation activity toward amides in the
presence of a stoichiometric amount of pinacolborane (Figure
1, top).2d,e Manganese has also been employed as a Lewis acid
in the presence of mild reductants such as pinacolborane or
hydrosilane.2f Furthermore, hydrosilanes can be used as
reductants under basic conditions, and they are therefore
versatile mild reductants that can be used under both acidic
and basic conditions.2g,h However, there are no reports of
amide reduction using only hydrosilanes. Therefore, we
focused on an electrochemical methodology to generate a
reactive intermediate to harness hydrosilanes as stand-alone
reductants without any rare metal- or borate-based activators
(Figure 1, bottom).
Redox-based methodologies have enabled various molecular
transformations via unique reactive intermediates.3 Photo- or
electrochemically initiated single-electron transfer (SET)
produces radical ion species that can be used for both
oxidation and reduction reactions. In particular, electro-
chemical reactions have a wide potential window, so various
substrates can be activated by electrodes. Previously, electro-
chemical amide reduction was reported using a Hg cathode or
strong acidic conditions;4a however, heavy metal-based
electrode materials should be avoided due to their high
Figure 1. Reported tactics for amide reduction.
toxicity. To optimize these classical conditions, Waldvogel and
co-workers established Pb cathode-mediated deoxygenation of
amides with minimum corrosion of Pb.4b,c From these
perspectives, we challenged ourselves to develop an electro-
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: April 22, 2021
https://doi.org/10.1021/acs.joc.1c00931
J. Org. Chem. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Article
a
chemical reduction method for amides by using hydrosilanes as
reductants without any corrosive heavy metal cathodes.
Table 2. Further Optimization Using an Indoline Substrate
RESULTS AND DISCUSSION
First, we explored suitable conditions for amide reduction
using compound 1 as a model substrate (Table 1). Electrolysis
■
a
Table 1. Optimization of Electrochemical Reduction
b
entry
deviation from the standard condition
yield (%)
1
2
3
4
5
6
7
8
none
53
47
22
0
0
61
83
51
trace
0
trace
trace
51
82
95
72
41
0
NR
divided cell (in cathode chamber)
Ph2SiH2 instead of PhSiH3
(EtO)3SiH instead of PhSiH3
Et3SiCl instead of PhSiH3
4 F/mol, Bu4NI (0.1 M)
4 F/mol, Bu4NBr (0.1 M)
4 F/mol, Bu4NCl (0.1 M)
4 F/mol, LiClO4 (0.1 M)
4 F/mol, NH4I (0.1 M)
Me4NI (0.1 M)
Me4NBr (0.1 M)
Et4NI (0.1 M)
Et4NBr (0.1 M)
5 F/mol, Et4NBr (0.1 M)
(+)GC-GC(−)
b
entry
deviation from the standard condition
none
0 °C
yield (%)
1
2
16
10
3
4
−40 °C
(+)Al-BDD(−)
trace
32
9
5
(+)Zn-BDD(−)
34
10
11
12
13
14
15
16
17
18
19
6
7
(+)Zn-BDD(−), Ar bubbling
entry 6 and 7 F/mol
63
83
8
entry 6 and 9 F/mol
42
9
entry 7, Et3SiH instead of PhSiH3
entry 7, PMHS instead of PhSiH3
entry 7, (+)Zn-GC(−)
entry 7, divided cell (in the cathode chamber)
entry 7, Bu4NClO4 (0.1 M)
3
5
79
trace
65
10
11
12
13
(+)Pt−Pt(−)
H2 bubbling without PhSiH3
without electrolysis
a
All reactions were carried out on a 0.5 mmol scale. PMHS represents
b
polymethylhydrosiloxane. Determined by 1H NMR by using
benzaldehyde as an internal standard.
a
All reactions were carried out on a 0.5 mmol scale of benzamide.
b
Determined by 1H NMR by using benzaldehyde as an internal
standard.
and 3). These results indicated that the anodically generated
halonium ions derived from the electrolyte inhibit the desired
reaction pathways. Therefore, we used sacrificial electrodes (Al
and Zn), and the yield was increased (entries 4−8). Other
hydrosilanes still gave poor yields (entries 9 and 10), and BDD
remained the best cathode material (entry 11). In the case of
compound 2, electrochemical reduction did not occur in a
divided cell (entry 12), and we considered that compounds 1
and 2 were reduced through different reaction pathways.
Finally, we found that amide reduction also occurred using a
Bu4NClO4 electrolyte, so that a halogen source was not
necessary under sacrificial anode conditions (entry 13).
Next, we performed a mechanistic study. The reduction
wave for compound 2 was observed at −2.35 V, but N-acetyl
indoline was not reduced under the same conditions (Figure
2A). This indicated that the benzoyl group has a crucial role in
enhancing electrochemical amide reduction. A cyclic voltam-
mogram for phenylsilane and Et4NBr indicated that oxidation
of bromine first occurred using a BDD anode (Figure 2B).
Furthermore, a catalytic current associated with phenylsilane
was observed in the presence of Et4NBr.
by boron-doped diamond (BDD) electrodes5 in the presence
of phenylsilane gave the product in moderate yield (entry 1). A
control experiment using a divided cell indicated that the
reaction was initiated by cathodic reduction (entry 2). Other
hydrosilane sources did not improve the yield (entries 3−5).
We found that employing Bu4NBr as the electrolyte and
increasing the electrical current gave a yield better than that
obtained using iodine or chlorine (entries 6−8). However,
Bu4NBr was difficult to remove, so further optimization was
required. The Lewis acid lithium perchlorate also gave a poor
yield (entry 9). Next, we changed the alkyl chain length in the
ammonium cation moiety and found that Et4NBr was a
suitable electrolyte (entries 10−15). BDD electrodes gave a
better yield than glassy carbon (GC) or platinum (Pt), but we
found that hydrosilane and an electrical current were necessary
for the reaction (entries 16−19).
However, we quickly discovered that the optimized
conditions could not be applied to indoline derivatives,
presumably due to the instability of benzylindoline under
these oxidative conditions.6 The standard conditions gave poor
yields and multiple byproducts due to the high reactivity of the
electron-rich indoline ring (Table 2, entry 1, compounds a−f),
and a lower temperature did not improve the yield (entries 2
Control experiments were also performed (Scheme 1). An
electrolyzed solution of phenylsilane has no reductive activity
toward compound 2, and we considered that the organo-
metallic reductant (ZnH2) was not generated in situ using a
B
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as a main hydride source under these electrochemical
conditions (Scheme 1C).
On the basis of these results, a plausible mechanism is
proposed as shown in Figure 3A. Using a BDD anode, the
anodically generated bromine radicals couple with phenylsilane
and produce HBr and a silyl radical species via a hydrogen
atom transfer (HAT) pathway.7 The resulting silyl radicals
react with cathodically generated ketyl radicals B to form
alkoxide C, which is immediately converted into carbanion D
by [1,2]-Brook rearrangement via pentavalent silicate.8 These
anions are oxidized to form iminium cations E at the anode,
which are then reduced to F by intramolecularly tethered
hydrosilyl groups. Successive elimination and reduction
processes give the desired benzylamine H through a whole
“oxidative reduction” pathway. In our screening for counter-
anions for the supporting electrolyte (Table 1, entries 6−8),
the yield with bromine was better than that with iodine or
chlorine. The bond dissociation energy for HBr (366 kJ/mol)
is close to that for the Si−H bond of phenylsilane (374 kJ/
mol).9 On the contrary, the energy gaps of HI (298 kJ/mol)
and HCl (431 kJ/mol) are smaller or larger than those of HBr
and phenylsilane. The more reactive Cl radical would cause
undesired overreaction, and therefore, we considered that the
energetic similarity between the bromine radical species and
phenylsilane is suitable for silyl radical generation during the
HAT event. The reaction in the divided cell (anode chamber)
gave a trace yield, presumably due to inhibition of cathodic
reduction, decreasing the population of bromine radical
species. Thus, regeneration of HBr to bromine anions in the
undivided cell system is desirable.
Figure 2. (A) Cyclic voltammogram for each compound (2 mM) in
0.05 M MeCN/Bu4NClO4. (B) Catalytic current for phenylsilane in
the presence of Et4NBr (each at 2 mM).
For a Zn sacrificial anode, the reaction is initiated by the
same radical anion species J (Figure 3B). As shown in Figure
3A, the benzoyl moiety is necessary for the radical anion
species to be generated. Therefore, we considered that the
radical anions are initially localized at the phenyl moieties of
the benzoyl groups, and intramolecular SET gives ketyl radical
K. On the anode side, erosive zinc ions are trapped by Br
anions to produce Lewis acid ZnBr2 in situ. Reaction with K
gives benzyl radicals L. Zinc ions also act as one-electron
oxidizers for L, and the resulting iminium cations M are then
reduced by phenylsilane. The participation of the lone pair on
nitrogen gives iminium cations O from hemiaminal N, and
subsequent reduction gives benzylamine P. We considered that
the formation of the zinc complex plays a crucial role in this
elimination process to enhance the leaving ability of oxygen.
The pKa value for the conjugate acid of compound 2a is
thought to be lower than that for 1a (9.48 in water)10 because
the lone pair of the nitrogen is delocalized on the indoline ring
due to resonance, and thus, the lone pair participation in 2
cannot occur as easily. The deuterated compound was
generated in a 51% ratio in the control experiment (Scheme
1C), and this indicated that the Hofmann elimination of the
electrolyte by cathodic reduction (Et4N+ to Et3N + ethylene +
1/2H2) and continuous hydrogen insertion into iminium cation
intermediate M or O also contributed to this amide reduction
process.
Scheme 1. Control Experiments
Finally, we demonstrated the scope of our electrochemical
amide reduction (Table 3). Model substrates 1 and 2 gave
good isolated yields (compounds 1a and 2a, respectively).
Electron-donating groups (alkyl, methoxy, and methylene-
dioxy) on the benzoyl moiety were tolerated despite the
instability of the resulting electron-rich benzyl moiety toward
acidic or oxidative conditions (compounds 3−5). Alkyl sulfide
zinc anode (Scheme 1A). The combination of phenylsilane
and ZnBr2 also produced no reaction, so ZnBr2 was not
directly involved in the reduction process (Scheme 1B).
Phenylsilane-d3 gave deuterated benzylamine 2b (monodeu-
terated) and 2c (dideuterated), indicating that hydrosilane acts
C
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Figure 3. Plausible reaction mechanism using (A) a BDD anode and (B) a Zn anode.
a
Table 3. Substrate Scope of Amide Reduction
a
b
All reactions were performed on a 0.5 mmol scale, and yields were determined by isolated weights. BDD electrodes were used as the anode and
c
d
cathode. An Al anode was used instead of a Zn anode. NMP (1 mL) was used as the co-solvent.
D
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vacuo. The resulting crude product was purified by silica gel column
chromatography.
and highly electron-withdrawing pyridine-tethered substrates
also gave the desired products (compounds 6 and 7). The π-
extended naphthyl moiety was tolerated (compound 8). Ring-
expanded or aniline-tethered amides gave poor yields due to
the weak basicity of nitrogen atoms and the resulting
competitive debenzylation (compounds 9 and 10). We
considered more Lewis acidic AlBr3 would assist in
deoxygenation events (intermediate N to O). As we expected,
an Al anode improves the yield. An aliphatic amide, piperidine,
could be reduced (compound 11), and electron-rich hetero-
cycles (benzofuran and benzothiophene) were tolerated
(compounds 12 and 13). Unfortunately, halogen and nitro
substituents were reduced to corresponding benzoyl or p-
aminobenzoyl groups (compounds 14−16). As we expected
on the basis of a cyclic voltammetry analysis, N-acetyl indoline
also gave no desired product (compound 17). The reaction
was applied to the natural alkaloid ( )-evodiamine, and the
desired product was obtained despite the presence of multiple
unstable electron-withdrawing benzylic aminal moieties
(compound 18). In this case, an Al anode also gave relatively
good yield compared with that seen with Zn. The cytotoxic
activity of the resulting dihydro-evodiamine toward breast
cancer cells is stronger than that of the parent compound;11
thus, our electrochemical methodology demonstrated access to
this pharmaceutically relevant molecule.
Method B. Compounds 1, 2, and S3−S13 were used as substrates.
The zinc anode (0.2 mm thickness) was replaced with the BDD
anode, and the procedure described for method A was used.
Indolin-1-yl(phenyl)methanone (2). To a solution of indoline
(1.12 mL, 10 mmol) in CH2Cl2/H2O [50 mL, 4:1 (v/v)] were added
NaHCO3 (2.52 g, 30 mmol) and benzoyl chloride (1.73 mL, 15
mmol), and the mixture was vigorously stirred at rt for 2.5 h. To the
resulting mixture was added H2O, and the mixture was extracted with
CH2Cl2 (3 × 15 mL). The organic layer was washed three times with
aqueous 1 M HCl and dried over anhydrous Na2SO4. After
concentration in vacuo, the crude product was recrystallized from
3:1 hexane/EtOAc, and 1.54 g of the title compound was obtained as
a brown needle crystal (6.91 mmol, 69%): 1H NMR (600 MHz,
CDCl3) δ 8.23−7.42 (7H, m, Ar), 7.22−7.21 (1H, d, Ar, J = 7.56 Hz),
7.03 (1H, s, br, Ar), 4.08 (2H, s, br, H-2), 3.14−3.11 (2H, t, H-1, J =
8.94 Hz, 17.2 Hz). This is a known compound.12a
[4-(tert-Butyl)phenyl](indolin-1-yl)methanone (S3). To a
suspension of 4-tert-butylbenzoic acid (534.7 mg, 3 mmol) in
CH2Cl2 (10 mL) were added indoline (224 μL, 2 mmol), NEt3 (836
μL, 6 mmol), HOBt (324 mg, 2.4 mmol), EDCI·HCl (460 mg, 2.4
mmol), and DMAP (24.4 mg, 0.2 mmol), and the mixture was stirred
at rt for 12 h. The reaction was quenched with saturated aqueous
NaHCO3, and the mixture extracted with EtOAc (3 × 15 mL). The
organic layer was washed with saturated aqueous NaHCO3 and
aqueous 1 M HCl and dried over anhydrous Na2SO4. After
concentration in vacuo, the resulting residue was recrystallized from
hexane, and 290 mg of the title compound was obtained as a white
1
CONCLUSION
solid (1.04 mmol, 52%): H NMR (600 MHz, DMSO-d6, 80 °C) δ
■
7.70 (1H, s, br, Ar), 7.51 (4H, m, Ar), 7.27−7.25 (1H, d, Ar, J = 7.56
Hz), 7.15−7.12 (1H, t, Ar, J = 7.56, 15.8 Hz), 7.03−7.01 (1H, t, Ar, J
= 7.56, 14.4 Hz), 4.03−4.01 (2H, t, H-2, J2−1 = 8.25 Hz, Jgem = 16.5
Hz), 3.14−3.07 (2H, m, H-1, overlapped with residual solvent peak),
1.34 (9H, s, C(CH3)3); 13C{1H} NMR (151 MHz, DMSO-d6, 80 °C)
δ 167.8, 152.5, 142.5, 134.0, 132.2, 126.4, 126.3, 124.7, 124.5, 123.1,
116.0, 49.9, 34.2, 30.6, 27.3; HRMS (ESI) m/z [M + Na]+ calcd for
C19H21NNaO+ 302.1515, found 302.1502; mp 104 °C.
We developed an electrochemical method for the amide
reduction reaction. Electrochemically activated substrates were
reacted with a hydrosilane, and the corresponding amines were
obtained without any expensive catalysts or toxic heavy metals.
This study provides novel insights for sustainable amide
reduction methodologies.
EXPERIMENTAL SECTION
Indolin-1-yl(4-methoxyphenyl)methanone (S4). To a solu-
tion of indoline (336 μL, 3 mmol) in pyridine (30 mL) was added 4-
methoxybenzoyl chloride (614 mg, 3.6 mmol), and the mixture was
stirred at rt for 13 h. To the reaction mixture was added aqueous 1 M
HCl, and the mixture was extracted with EtOAc (3 × 15 mL). The
organic layer was washed with aqueous 1 M HCl and saturated
aqueous NaHCO3 and dried over anhydrous Na2SO4. After
concentration in vacuo, recrystallization from 5:1 hexanes/EtOAc
gave 497.3 mg of the title compound as a white solid (1.96 mmol,
■
General Information. All reactions were performed under an
argon atmosphere, unless otherwise noted. H and 13C NMR spectra
1
were recorded in CDCl3 and DMSO-d6 by using a JEOL ECA-600
spectrometer (1H, 600 MHz; 13C, 151 MHz) or JEOL ECA-400
spectrometer (1H, 400 MHz; 13C, 100 MHz). Tetramethylsilane (1H
NMR, δ 0.00), CDCl3 (1H NMR, δ 7.26; 13C NMR, δ 77.16), DMSO
(1H NMR, δ 2.50; 13C NMR, δ 39.52), and CH3NO2 (1H NMR, δ
4.34) were used as internal standards. Mass spectra were recorded on
a JEOL JMS T-100LP mass spectrometer. Cyclic voltammetry was
carried out on an ALS electrochemical analyzer 611 DN. The
oxidation potential was measured with a glassy carbon rod as the
anode, a platinum wire as the cathode, and Ag/AgCl as the reference
electrode. The melting point was measured by SMP10 (Stuart
Equipment). Merck precoated silica gel F254 plates (thickness of 0.25
mm) were used for thin-layer chromatography (TLC). All materials
were obtained from TCI Fine Chemicals, Wako Pure Chemical
Industries, Kanto Chemical, and Sigma-Aldrich and used without
purification. N,N-Diethylbenzamide (1) and 1-benzoylpiperidine
(S11) were purchased from TCI.
Electrochemical Reduction. Method A. A solution of a substrate
(0.5 mmol), phenylsilane (2 mmol), and Et4NBr (210 mg, 1 mmol)
in MeCN (10 mL) was equipped with a zinc plate anode (40 mm ×
20 mm) and a boron-doped diamond (BDD) plate cathode (80 mm
× 20 mm). The cathode surface area in the solution phase was 20 mm
× 20 mm (4 cm2), and the current was 20 mA. Thus, the current
density was estimated to be 5 mA/cm2. After being exposed to 7 F/
mol (337.75 C) of electricity by current potential (5 mA/cm2), to the
reaction mixture was added saturated aqueous NaHCO3, and the
precipitate was removed by Celite pad filtration. The Celite cake was
washed with EtOAc, and the filtrate was washed with brine. The
organic layer was dried over anhydrous Na2SO4 and concentrated in
1
65%): H NMR (600 MHz, CDCl3) δ 7.56 (2H, m, Ar), 7.22−6.93
(6H, m, Ar), 4.14−4.11 (2H, t, H-2, J = 8.25 Hz), 3.87 (3H, s,
-OCH3), 3.13−3.10 (2H, t, H-1, J = 8.25 Hz). This is a known
compound.12b
Indolin-1-yl(4-methoxybenzo[d][1,3]dioxol-5-yl)methanone
(S5). This compound was synthesized in our previous study.12c
Indolin-1-yl[4-(methylthio)phenyl]methanone (S6). To a
suspension of 4-methylthiobenzoic acid (505 mg, 3 mmol) and
DMF (3 drops) in toluene (30 mL) was added SOCl2 at 0 °C. After
the mixture was stirred at rt for 16 h, the solvent was removed in
vacuo, and the resulting residue was dissolved in pyridine (30 mL).
To the solution was added indoline (504 μL, 4.5 mmol), and the
mixture was stirred at rt for 3 h. The reaction was quenched with
aqueous 1 M HCl, and the mixture was extracted with EtOAc (3 × 20
mL). The organic layer was washed with aqueous 1 M HCl and
saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. After
concentration in vacuo, recrystallization from hexanes/EtOAc gave
590.7 mg of the title compound as a colorless solid (2.19 mmol,
73%): 1H NMR (400 MHz, CDCl3) δ 7.76−7.49 (2H, m, Ar), 7.29−
7.0 (6H, m, Ar, overlapped with residual solvent), 4.11 (2H, m, H-2),
3.14−3.10 (2H, t, H-1, J = 8.24, 8.0 Hz), 2.53 (3H, s, -SCH3);
13C{1H} NMR (151 MHz, CDCl3) δ 168.6, 142.8, 142.2, 133.2,
128.0, 127.4, 125.7, 125.1, 124.0, 117.1, 50.8, 28.3, 15.3; HRMS (ESI)
E
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m/z [M + Na]+ calcd for C16H15NNaOS+ 292.0772, found 292.0750;
mp 134 °C.
Ar), 7.82−7.79 (1H, m, Ar), 7.45 (1H, s, Ar), 7.39 (2H, m, Ar), 3.69
(4H, m, br, H-2, H-6), 1.74−1.65 (6H, m, H-3, H-4, H-5); 13C{1H}
NMR (CDCl3, 151 MHz) δ 163.7, 140.0, 138.7, 137.2, 125.5, 124.7,
124.5, 124.4, 122.3, 48.8, 44.0, 26.3, 24.6; HRMS (ESI) m/z [M +
H]+ calcd for C14H16NOS+ 246.0953, found 246.0973; mp 127 °C.
N-Benzyl-N-ethylethanamine (1a). Method A was used for
compound 1, and purification by silica gel column chromatography
(1:1 hexanes/EtOAc) gave 63.7 mg of the title compound as a
colorless oil (0.39 mmol, 78%): 1H NMR (600 MHz, CDCl3) δ
7.34−7.29 (4H, m, Ar), 7.24−7.22 (1H, m, Ar), 3.56 (2H, s,
-NCH2Ar), 2.54−2.50 (4H, q, -NCH2CH3 × 2, J = 6.87, 7.22 Hz),
1.05−1.03 (6H, t, -NCH2CH3 × 2, J = 6.87, 7.22 Hz). This is a
known compound.12h
1-Benzylindoline (2a). Method B was used for compound 2, and
purification by silica gel column chromatography (12:1 hexanes/
EtOAc) gave 85.8 mg of the title compound as a brown oil (0.41
mmol, 82%). The 1 mmol scale reaction was carried out in 20 mL of
MeCN/Et4NBr (0.1 M) by using the same electrochemical condition,
and 128.7 mg of the title compound was obtained (0.61 mmol, 61%):
1H NMR (600 MHz, CDCl3) δ 7.37−7.32 (4H, m, Ar), 7.28−7.27
(1H, m, Ar), 7.10−7.09 (1H, d, Ar, J = 6.87 Hz), 7.07−7.04 (1H, t,
Ar, J = 8.25, 7.90 Hz), 6.68−6.65 (1H, t, Ar, J = 7.56 Hz), 6.52−6.50
(1H, d, Ar, J = 8.25 Hz), 4.25 (2H, s, -NCH2Ar), 3.33−3.30 (2H, t,
H-2, J = 8.25, 8.59 Hz), 2.99−2.96 (2H, t, H-1, J = 8.25, 8.59 Hz).
This is a known compound.12i
Indolin-1-yl(pyridin-2-yl)methanone (S7). The same reaction
procedure that was used for S3 was used for 2-picolinic acid and
indoline (without the 1 M HCl wash). Purification by silica gel
column chromatography (2:1 hexanes/EtOAc) gave 408.6 mg of the
1
title compound as a purple amorphous solid (1.82 mmol, 91%): H
NMR (600 MHz, CDCl3, 50 °C) δ 8.67−8.66 (1H, d, Ar, J = 4.81
Hz), 8.32 (1H, s, br, Ar), 7.94−7.91 (2H, m, Ar), 7.462−7.457 (1H,
m, Ar), 7.23−7.22 (1H, m, Ar, overlapped with residual solvent), 7.07
(1H, s, br, Ar), 4.37−4.34 (2H, t, H-2, J = 8.94, 8.59 Hz), 3.18−3.16
(2H, t, H-1, J = 8.94, 8.59 Hz). This is a known compound.12d
Indolin-1-yl(naphthalen-2-yl)methanone (S8). The same
reaction procedure that was used for compound S6 was used for 2-
naphthoic acid and indoline. Recrystallization from hexanes/EtOAc
gave 624.1 mg of the title compound as colorless crystals (2.28 mmol,
1
76%): H NMR (400 MHz, CDCl3) δ 8.07 (1H, s, Ar), 7.93−7.89
(4H, m, Ar), 7.64−7.52 (4H, m, Ar), 7.24−7.22 (1H, m, Ar), 7.03
(1H, s, br, Ar), 4.16 (2H, s, br, H-2), 3.17−3.13 (2H, t, H-1, J = 8.24
Hz); 13C{1H} NMR (151 MHz, CDCl3) δ 169.1, 142.8, 134.4, 134.2,
132.9, 128.8, 128.6, 128.0, 127.5, 126.9, 125.1, 124.4, 124.1, 117.6,
50.8, 28.3; HRMS (ESI) m/z [M + Na]+ calcd for C19H15NNaO+
296.1051, found 296.1022; mp 149 °C.
[3,4-Dihydroquinolin-1(2H)-yl](3,4-dimethoxyphenyl)-
methanone (S9). To a solution of 1,2,3,4-tetrahydroisoquinoline
(266 μL) in pyridine (10 mL) were added 3,4-dimethoxybenzoyl
chloride (480 mg, 2.4 mmol) and DMAP (24.4 mg, 0.2 mmol), and
the mixture was stirred at rt for 14 h. The reaction was quenched with
1 M HCl, and the mixture was extracted with EtOAc (3 × 15 mL).
The organic layer was washed with aqueous 1 M HCl and saturated
aqueous NaHCO3 and dried over Na2SO4. The resulting crude
product was purified by amino silica gel column chromatography
(NH form, 2:1 to 3:2 hexanes/EtOAc), and 591.3 mg of the title
1-[4-(tert-Butyl)benzyl]indoline (3). Method B was used for
compound S3, and purification by silica gel column chromatography
(30:1 to 20:1 hexanes/EtOAc) gave 85.3 mg of the title compound as
1
a colorless oil (0.32 mmol, 63%): H NMR (CDCl3, 600 MHz) δ
7.35 (2H, d, Ar, J = 8.16 Hz), 7.29 (2H, d, Ar, J = 8.16 Hz), 7.03−
7.12 (2H, m, Ar), 6.66 (1H, t, Ar, J = 7.3 Hz), 6.53 (1H, d, Ar, J = 7.8
Hz, 1H), 4.22 (2H, s, -ArCH2N-), 3.30 (2H, t, -NCH2CH2-, J = 8.25
Hz), 2.96 (2H, t, -CH2CH2Ar-, J = 8.25 Hz), 1.32 (9H, s,
-ArC(CH3)3); 13C{1H} NMR (CDCl3, 151 MHz) δ 152.6, 150.0,
135.4, 130.0, 127.6, 127.3, 125.4, 124.5, 117.5, 107.0, 53.5, 53.2, 34.5,
31.4, 28.5; HRMS (ESI) m/z [M + Na]+ calcd for C19H23NNa+
288.1728, found 288.1729.
1
compound was obtained as a white solid (1.99 mmol, 99.5%): H
NMR (600 MHz, CDCl3) δ 7.15−7.14 (1H, d, Ar, J = 6.87 Hz), 7.0−
6.97 (1H, t, Ar, J = 7.56, 15.1 Hz), 6.93−6.92 (2H, m, Ar), 6.89−6.87
(1H, t, Ar, J = 7.56, 15.1 Hz), 6.71−6.68 (1H, t, Ar, J = 8.25, 7.90
Hz), 3.92−3.90 (2H, t, H-3, J = 6.87, 13.8 Hz), 3.86 (3H, s, -OCH3),
3.72 (3H, s, -OCH3), 2.84−2.82 (2H, t, H-1, J = 6.87, 13.1 Hz),
1-(4-Methoxybenzyl)indoline (4). Method B was used for
compound S4, and purification by silica gel column chromatography
(12:1 hexanes/EtOAc) gave 48.5 mg of the title compound as a
2.07−2.03 (2H, quin, H-2, J = 6.87, 6.53 Hz). This is a known
compound.12e
1
N-Methyl-N-phenylbenzo[d][1,3]dioxole-5-carboxamide
(S10). To a solution of N-methylaniline (1.08 mL, 10 mmol) in
CH2Cl2 (50 mL) were added NEt3 (4.18 mL, 30 mmol) and
piperonyloyl chloride (1.85 g, 10 mmol), and the mixture was stirred
at rt for 16 h. The resulting mixture was quenched with saturated
aqueous NaHCO3 and extracted with CH2Cl2 (3 × 20 mL). The
organic layer was washed twice with aqueous 1 M HCl and dried over
anhydrous Na2SO4. After concentration in vacuo, the resulting crude
product was purified by silica gel column chromatography (1:1
hexanes/EtOAc), and 2.48 g of the title compound was obtained as a
colorless oil (0.2 mmol, 41%): H NMR (CDCl3, 600 MHz) δ 7.28
(2H, d, Ar, J = 8.25 Hz), 7.09 (1H, d, Ar, J = 7.56 Hz), 7.05 (1H, t,
Ar, J = 7.56 Hz), 6.87 (2H, d, Ar, J = 8.25 Hz), 6.66 (1H, t, Ar, J =
7.56 Hz), 6.53 (1H, d, Ar, J = 7.56 Hz), 4.19 (2H, s, -ArCH2N-), 3.81
(3H, s, -OCH3), 3.27 (2H, t, -NCH2CH2-, J = 8.25 Hz), 2.95 (2H, t,
-CH2CH2Ar-, J = 8.25 Hz). This is a known compound.13a
1-[(4-Methoxybenzo[d][1,3]dioxol-5-yl)methyl]indoline (5).
Method B was used for compound S5, and purification by silica gel
column chromatography (10:1 hexanes/EtOAc) gave 78.9 mg of the
title compound as a colorless oil (0.28 mmol, 56%): 1H NMR
(CDCl3, 400 MHz) δ 7.09−7.04 (2H, m, Ar), 6.82−6.80 (1H, d, Ar, J
= 8.24 Hz), 6.66−6.63 (1H, t, Ar, J = 7.33 Hz), 6.57−6.54 (1H, d, Ar,
J = 7.79 Hz), 6.51−6.49 (1H, d, Ar, J = 7.79 Hz), 4.18−4.16 (2H, m,
-NHCH2Ar), 4.0 (3H, s, -OCH3), 3.37−3.33 (2H, t, H-2, J = 8.24
Hz), 2.98−2.94 (2H, t, H-1, J = 8.24 Hz); 13C{1H} NMR (101 MHz,
CDCl3) δ 152.7, 148.7, 141.9, 136.7, 134.9, 130.0, 127.9, 127.4, 124.5,
123.8, 122.2, 117.4, 107.1, 102.5, 101.1, 59.8, 53.7, 48.4, 28.7; HRMS
1
yellow oil (9.7 mmol, 97%): H NMR (600 MHz, CDCl3) δ 7.27−
7.26 (2H, m, Ar), 7.17−7.15 (1H, t, Ar, J = 7.56, 15.1 Hz), 7.05−7.04
(2H, m, Ar), 6.83−6.81 (2H, m, Ar), 6.58−6.56 (1H, d, Ar, J = 8.25
Hz), 5.90 (2H, s, -OCH2O-), 3.47 (3H, s, -NCH3). This is a known
compound.12f
Benzofuran-2-yl(piperidin-1-yl)methanone (S12). The same
reaction procedure that was used for S3 was used for benzofuran-2-
carboxylic acid and piperidine. Silica gel chromatography (2:1 to 1:1
hexanes/EtOAc) gave 631.3 mg of the titled compound as a white
solid (2.8 mmol, 92%): 1H NMR (DMSO-d6, 600 MHz) δ 7.73 (1H,
d, Ar, J = 7.56 Hz), 7.65 (1H, d, Ar, J = 8.25 Hz), 7.45−7.42 (1H, m,
Ar), 7.30−7.35 (2H, m, Ar), 3.64 (4H, m, br, H-2, H-6), 1.67−1.64
(2H, m, H-4), 1.59−1.55 (4H, m, H-3, H-5). This is a known
compound.12g
+
(ESI) m/z [M + Na]+ calcd for C17H17NNaO3 306.1101, found
306.1084.
1-[4-(Methylthio)benzyl]indoline (6). Method B was used for
compound S6, and purification by silica gel chromatography (12:1
hexanes/EtOAc) gave 50.9 mg of the title compound as a colorless oil
1
(0.20 mmol, 40%): H NMR (CDCl3, 400 MHz) δ 7.26−7.32 (2H,
m, Ar), 7.20−7.25 (2H, m, Ar), 7.01−7.12 (2H, m, Ar), 6.64−6.70
(1H, m, Ar), 6.50 (1H, d, Ar, J = 7.8 Hz), 4.20 (2H, s, -NCH2Ar),
3.29 (2H, t, H-2, J = 8.24 Hz), 2.96 (2H, t, H-1, J = 8.24 Hz), 2.48
(3H, s, -SCH3); 13C{1H} NMR (CDCl3, 101 MHz) δ 152.6, 137.1,
135.6, 130.2, 128.6, 127.4, 127.0, 124.7, 117.9, 107.2, 53.7, 53.4, 28.7,
Benzo[b]thiophen-2-yl(piperidin-1-yl)methanone (S13).
The same reaction procedure that was used for S3 was used for
benzo[b]thiophen-2-carboxylic acid and piperidine. Recrystallization
from hexanes/EtOAc gave 434.5 mg of the title compound as a white
solid (1.8 mmol, 59%): 1H NMR (CDCl3, 600 MHz) δ 7.85 (1H, m,
F
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16.2; HRMS (ESI) m/z [M + Na]+ calcd for C16H17NNaS+ 278.0974,
found 278.0993.
54.4, 25.9, 24.3; HRMS (ESI) m/z [M + H]+ calcd for C14H18NS+
232.1160, found 232.1172; mp 68 °C.
14-Methyl-5,7,8,13,13b,14-hexahydroindolo[2′,3′:3,4]-
pyrido[2,1-b]quinazoline (18). Method B was used for ( )-ebodi-
amine (1 mL of NMP was used as the co-solvent with 9 mL of
MeCN) using an Al anode, and purification by silica gel column
chromatography (4:1 hexanes/EtOAc) gave 47 mg of the title
1-(Pyridin-2-ylmethyl)indoline (7). Method B was used for
compound S7, and purification by silica gel column chromatography
(3:1 hexanes/EtOAc) gave 53.8 mg of the title compound as a yellow
1
oil (0.26 mmol, 52%): H NMR (CDCl3, 600 MHz) δ 8.58−8.57
(1H, d, br, J = 4.81 Hz), 7.66−7.64 (1H, dt, Ar, J = 1.37, 7.56 Hz),
7.42−7.41 (1H, d, Ar, J = 8.25 Hz), 7.19−7.17 (1H, m, Ar), 7.12−
7.11 (1H, d, Ar, J = 6.87 Hz), 7.05−7.00 (1H, m, Ar), 6.71−6.64 (1H,
m, Ar), 6.45−6.44 (1H, d, Ar, J = 7.56 Hz), 4.40 (2H, s, -NCH2Ar),
3.56−3.43 (2H, td, H-2, J = 8.25 Hz), 3.04−3.02 (2, t, H-1, J = 8.25
Hz); 13C{1H} NMR (151 MHz, CDCl3) δ 159.0, 152.4, 149.4, 136.9,
130.0, 127.5, 127.3, 124.8, 124.6, 122.2, 121.9, 118.0, 109.6, 107.1,
55.8, 54.2, 30.0, 28.8; HRMS (ESI) m/z [M + Na]+ calcd for
C14H14N2Na+ 233.1049, found 233.1068.
1
compound as a white solid (0.16 mmol, 32%): H NMR (600 MHz,
DMSO-d6) δ 11.1 (1H, s, -NH), 7.45−7.44 (1H, d, Ar, J = 7.56 Hz),
7.35−7.33 (1H, d, Ar, J = 8.25 Hz), 7.14−7.11 (1H, t, Ar, J = 6.87
Hz), 7.09−7.06 (1H, t, Ar, J = 7.56 Hz), 7.02−7.01 (1H, d, Ar, J =
6.19 Hz), 6.99−6.97 (1H, t, Ar, J = 7.56 Hz), 6.95−6.93 (1H, d, Ar, J
= 8.25 Hz), 6.84−6.82 (1H, t, Ar, J = 6.19 Hz), 4.89 (1H, s, -NCHN-
), 3.93 (2H, s, -NCH2Ar), 3.27−3.24 (1H, m, -NCH2CHa(-Hb)Ar),
2.87−2.81 (1H, m, -NCH2CHa(-Hb)Ar), 2.78−2.72 (2H, m,
-NCH2CH2Ar), 2.65 (3H, s, -NCH3). This is a known compound.11
Phenylsilane-d3. LiAlD4 (1.0 g, 23.8 mmol) was placed in a
flame-dried round-bottom flask to which was added dry Et2O (80
mL) at 0 °C. To the resulting suspension was added trichlor-
ophenylsilane (2.08 mL, 13 mmol), and the mixture was refluxed for
30 h. The solvent was removed in vacuo at 0 °C, and the resulting
crude was distilled under reduced pressure (1 kPa, diaphragm pump).
The desired compound was collected with a cold trap (−40 °C), and
residual Et2O was removed by heating in an oil bath (60 °C). Finally,
54.1 mg of the title compound was obtained as a colorless 30% Et2O
solution (0.49 mmol, 4% yield, 99% D): 1H NMR (600 MHz,
CDCl3) δ 7.61−7.60 (2H, m, Ar), 7.43−7.40 (1H, m, Ar), 7.38−7.36
(2H, m, Ar). This is a known compound.13f
1-(Naphthalen-2-ylmethyl)indoline (8). Method B was used
for compound S8, and purification by silica gel chromatography (12:1
hexanes/EtOAc) gave 67.7 mg of the title compound as a yellow solid
1
(0.26 mmol, 52%): H NMR (CDCl3, 400 MHz) δ 7.77−7.86 (4H,
m, Ar), 7.41−7.54 (3H, m, Ar), 7.02−7.15 (2H, m, Ar), 6.65−6.72
(1H, m, Ar), 6.55 (1H, d, Ar, J = 7.8 Hz), 4.39 (2H, s, -NCH2Ar),
3.34 (2H, t, H-2, J = 8.24 Hz), 2.99 (2H, t, H-1, J = 8.24 Hz). This is
a known compound.13b
1-(3,4-Dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline (9).
Method B was used for compound S9 with an Al anode, and
purification by silica gel column chromatography (12:1 hexanes/
EtOAc) gave 34 mg of the title compound as a colorless oil (0.06
1
mmol, 12%): H NMR (CDCl3, 600 MHz) δ 7.0−6.97 (2H, m, Ar),
1-(Phenylmethyl-d)indoline (2b) and 1-(Phenylmethyl-d2)-
indoline (2c). Method B was used for compound 2 (26.8 mg, 0.12
mmol) in a MeCN/Et4NBr (0.1 M) solution (5 mL) in the presence
of PhSiD3 (0.49 mmol, 30% Et2O solution). Purification by silica gel
column chromatography (12:1 hexanes/EtOAc) gave 21 mg of the
inseparable mixture of 2b, 2c, and 2a as a brown oil (0.1 mmol, total
83% yield, 51% D): 1H NMR (600 MHz, CDCl3) δ 7.50−7.27 (5, m,
Ar), 7.14−7.08 (2H, m, Ar), 6.72−6.57 (2H, m, Ar), 4.28−4.25 (0.99
H, m, -NH2Ar and -NHDAr), 3.35 (2H, s, br, H-2), 2.99−2.96 (2H, t,
6.81−6.80 (3H, m, Ar), 6.59−6.54 (2H, m, Ar), 4.41 (2H, s,
-NCH2Ar), 3.86−3.84 (6H, m, -OCH3 × 2), 3.34−3.32 (2H, t, H-3,
J3−2 = 6.19, 11.7 Hz), 2.82−2.80 (2H, t, H-1, J1−2 = 6.87 Hz, Jgem
=
13.1 Hz), 2.02−1.98 (2H, quin, H-2, J2−3 = 6.19 Hz, J2−1 = 6.19 Hz);
13C{1H} NMR (151 MHz, CDCl3) δ 149.3, 148.0, 145.9, 131.5,
129.1, 127.3, 122.5, 118.7, 116.0, 111.3, 111.2, 109.9, 56.1, 56.0, 55.1,
49.8, 28.4, 22.5; HRMS (ESI) m/z [M + Na]+ calcd for
+
C18H21NNaO2 306.1465, found 306.1477.
H-1, J = 8.25 Hz); HRMS (ESI) m/z [M + H]+ calcd for C15H15DN+
(2b) 211.1346, found 211.1357; HRMS (ESI) m/z [M + H]+ calcd
for C15H14D2N+ (2c) 212.1408, found 212.1388.
N-(Benzo[d][1,3]dioxol-5-ylmethyl)-N-methylaniline (10).
Method B was used for compound S10 with an Al anode, and
purification by silica gel column chromatography (12:1 hexanes/
EtOAc) gave 57.9 mg of the title compound as a colorless oil (0.12
mmol, 24%): 1H NMR (CDCl3, 600 MHz) δ 7.23−7.21 (2H, m, Ar),
6.76−6.69 (6H, m, Ar), 5.93 (2H, s, -OCH2O-), 4.43 (2H, s,
-NCH2Ar), 2.98 (3H, s, -NCH3). This is a known compound.13c
1-Benzylpiperidine (11). Method B was used for N-benzoylpi-
peridine, and purification by silica gel column chromatography (2:3
hexanes/EtOAc) gave 75.8 mg of the title compound as a colorless oil
(0.43 mmol, 86%). Method A gave 74.5 mg of 11 (0.425 mmol,
85%): 1H NMR (CDCl3, 600 MHz) δ 7.45−7.23 (5H, m, Ar,
overlapped with residual solvent), 3.47 (2H, s, -NCH2Ar), 2.37 (4H,
s, br, H-2, H-6), 1.59−1.55 (4H, quint, H-3, H-5), 1.42 (2H, m, br,
H-4). This is a known compound.13d
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00931.
Spectral data of compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
1-(Benzofuran-2-ylmethyl)piperidine (12). Method B was
used for S12, and purification by silica gel column chromatography
(1:1 hexanes/EtOAc) gave 70.2 mg of the title compound as a
colorless oil (0.33 mmol, 65%): 1H NMR (CDCl3, 600 MHz) δ 7.51
(1H, d, Ar, J = 6.87 Hz), 7.47 (1H, d, Ar, J = 8.94 Hz), 7.25−7.18
(2H, m, Ar), 6.57 (1H, s, Ar), 3.65 (2H, s, -NCH2Ar), 2.59−2.34
(4H, m, br, H-2, H-6), 1.64−1.60 (4H, quint, H-3, H-5, J = 5.50 Hz),
1.53−1.34 (2H, m, br, H-4). This is a known compound.13e
1-(Benzo[b]thiophen-2-ylmethyl)piperidine (13). Method B
was used for S13, and purification by silica gel column
chromatography (6:1 to 4:1 hexanes/EtOAc) gave 101.6 mg of the
title compound as a yellow solid (0.45 mmol, 89%): 1H NMR
(CDCl3, 600 MHz) δ 7.78 (1H, d, Ar, J = 7.56 Hz), 7.67 (1H, d, Ar, J
= 7.56 Hz), 7.32−7.24 (2H, m, Ar), 7.12 (1H, s, Ar), 3.75 (2H, s,
-NCH2Ar), 2.46 (4H, m, br, H-2, H-6), 1.62−1.59 (4H, tt, H-3, H-5,
J = 5.50 Hz), 1.49−1.37 (2H, m, H-4); 13C{1H} NMR (CDCl3, 151
MHz) δ 144.1, 140.0, 139.7, 123.9, 123.7, 123.0, 122.3, 121.9, 58.6,
Kazuhiro Chiba − Department of Applied Biological Science,
Tokyo University of Agriculture and Technology, Tokyo 183-
8509, Japan; orcid.org/0000-0002-9580-5236;
Email: chiba@cc.tuat.ac.jp
Authors
Kazuhiro Okamoto − Department of Applied Biological
Science, Tokyo University of Agriculture and Technology,
Tokyo 183-8509, Japan; orcid.org/0000-0002-3865-
0362
Shingo Nagahara − Department of Applied Biological Science,
Tokyo University of Agriculture and Technology, Tokyo 183-
8509, Japan
Yasushi Imada − Department of Applied Biological Science,
Tokyo University of Agriculture and Technology, Tokyo 183-
8509, Japan
G
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Article
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of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway
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8087.
(8) Deng, Y.; Liu, Q.; Smith III, A. B. Oxidative [1,2]-Brook
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Energies; CRC Press: Boca Raton, FL, 2007. (b) Barber, M.;
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Am. Chem. Soc. 1957, 79, 5441−5444.
Risako Narita − Department of Applied Biological Science,
Tokyo University of Agriculture and Technology, Tokyo 183-
8509, Japan
Yoshikazu Kitano − Department of Applied Biological Science,
Tokyo University of Agriculture and Technology, Tokyo 183-
8509, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00931
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (Grants
19K22272 and 19H00930 to K.C. and Grant 20H03072 to
Y.K.), JST CREST Japan (JPMJCR19R2 to K.C.), and Grants-
in-Aid for JSPS Fellows (20J11925 to K.O. and 18J22018 to
Y.I.).
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