Electrochemical Synthesis of Cyanoformamides from Trichloroacetonitrile and Secondary Amines Mediated by the B12Derivative

Article abstract of DOI:10.1021/acs.joc.1c00837

The B₁₂derivative, heptamethyl cobyrinate, -mediated electrochemical synthesis of cyanoformamides has been developed. Aerobic oxygenation of the carbon-centered radical initiatedin situgeneration of the reactive acyl chloride intermediate, whic

Full text of DOI:10.1021/acs.joc.1c00837

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Electrochemical Synthesis of Cyanoformamides from
Trichloroacetonitrile and Secondary Amines Mediated by the B12
Derivative
Mohammad Moniruzzaman, Yoshio Yano, Toshikazu Ono, Kenji Imamura, Yoshihito Shiota,
Kazunari Yoshizawa, Yoshio Hisaeda,* and Hisashi Shimakoshi*
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ABSTRACT: The B12 derivative, heptamethyl cobyrinate, -mediated
electrochemical synthesis of cyanoformamides has been developed. Aerobic
oxygenation of the carbon-centered radical initiated in situ generation of the
reactive acyl chloride intermediate, which led to cyanoformamides in the
presence of an amine. This one-pot and scalable synthetic method has been
demonstrated with 41 examples up to 94% yields with 21 new compounds.
The mechanism of electrolysis mediated by the B12 derivative has been
proposed based on the DFT calculations.
yanoformamides are important synthetic targets for
versatile building blocks in the synthesis of lactams,1
Scheme 1. Overview of Cyanoformamides Synthesis
C
acrylonitriles,2 tetrazoles,3 unsymmetrical ketones,4 substituted
ureas,5 carbamoyl amidoximes,6 and pyrrole-2-carboxamide.7
The structural motif of cyanoformamides is also found in
antifouling compounds.8 Initially, cyanoformamides were
prepared using cyanogen,9 potassium cyanide,10 carbonyl
cyanide,11 dichlorosulfenyl chlorides,12 isonitroso Meldrum’s
acid,13 or tetracyanoethylene.14 Various advanced methods
have been reported in the past decade that aim to address the
safely implications without using toxic reagents as cyano
source, such as hypervalent iodine/NH4OAc (Scheme 1a),15a
phosphoryl trichloride (POCl3)/1-acyl-1-carbamoyl oximes
(Scheme 1b),15b trimethylsilyl cyanide (TMSCN)/carbamoyl
imidazoles (Scheme 1c),4,15c tert-butyl nitrite (tBuONO)/
trifluoropropanamides (Scheme 1d),15d CsF/N,N-disubsti-
tuted aminomalononitriles (Scheme 1e),15e and dichloroimi-
dazolidinedione (DCIDs)/1-acyl-1-carbamoyl oximes
(Scheme 1f).15f Considering the importance of cyanoforma-
mides in organic synthesis, the development of further
improved methods is desired.
Therefore, we envisaged that the electroorganic synthesis
may be applicable to cyanoformamides synthesis. Electro-
organic synthesis has attracted attention in organic synthesis
since it circumvents the use of chemical reductants and
oxidants by using an electric current.16 Recently, we developed
the unique electrochemical molecular transformation of the
trichlorinated methyl compound (R1-CCl3) to form the amide
in the presence of amine by the B12 derivative (heptamethyl
cobyrinate perchlorate, C1) in air (Scheme 1g).17 The reactive
acyl chloride should be formed as an intermediate from the R1-
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: April 12, 2021
https://doi.org/10.1021/acs.joc.1c00837
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© XXXX American Chemical Society
A

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CCl3 under aerobic conditions. Based on this molecular
transformation, cyanoformamides could be formed via
cyanoformyl chloride from the commercially available
trichloroacetonitrile (1) by the B12 derivative as a redox
mediator at room temperature in the air using the electro-
chemical method. The cyanoformyl chloride has an impact on
synthetic organic chemistry to transform various fine
chemicals,18 and its spectroscopic or theoretical analysis has
been investigated due to the unique chemical properties.19
Nevertheless, only a few studies have reported generating
cyanoformyl chloride that requires very harsh reaction
conditions by thermolysis or pyrolysis.18
We now report the C1-mediated one-pot electrochemical
synthesis of cyanoformamides from 1 in the presence of readily
available amines in the air at room temperature (Scheme 1h).
We commenced our studies by investigating reaction
conditions for the envisaged electrochemical dechlorination
of 1 in the presence of the diethylamine (Et2NH) by the
catalysis of C1 at −0.6 V vs Ag/AgCl in an undivided cell
equipped with carbon felt (CF) as the cathode, and zinc plate
(Zn) as the counter electrode in MeCN. After considerable
optimization of reaction conditions, the desired product,
diethylcarbamoyl cyanide (2a), was obtained with 70% yield in
which the amount of the 1 was 20 mM along with 200 mM of
the diethylamine (Table 1, entry 1).
occurred between C1 and O2/O2•− at the cathode and O2 that
may quench the active species Co(I); therefore, the yield
significantly decreased (Table 1, entry 6). When the Zn plate
was replaced with the Pt mesh, CF, Al rod, or Mg rod as the
counter electrode, the efficiency of the reaction rationally
decreased (Table 1, entry 7). The choice of solvent led to a
significant impact on the reaction outcome, and a drop in the
product (2a) yield was observed when MeOH, EtOH, DMF,
DMSO, or THF was used as the solvent instead of the MeCN
(Table 1, entry 8). Reducing the amount of Et2NH afforded a
decrease in the yield (Table 1, entry 9).
With the optimized reaction conditions in hand, the scope of
linear amines was explored as shown in Scheme 2. Several
Scheme 2. Scope of Linear Amines for Cyanoformamides
a
Synthesis
Table 1. Reaction Optimization
b
entry
derived from standard conditions
yield (%)
c
1
none
no catalyst
70
17
0
31
35
42
2
3
4
5
no applied potential
−0.9 V
CoIII{(C2C3)(DO)(DOH)pn}Br2 (C2)
under O2
d
6
7
8
9
Pt, CF, Al, Mg anode instead of Zn
MeOH, EtOH, DMF, DMSO, THF instead MeCN 0, 0, 21, 27, 58
0.1 M, 0.04 M of Et2NH instead of 0.2 M 44, 22
13, 13, 12, 14
a
Reaction conditions: C1 (0.13 mM), 1 (20.0 mM), Et2NH (0.2 M),
nBu4NClO4 (0.1 M), MeCN (10 mL), CF-cathode, Zn-plate anode,
undivided cell, applied potential was −0.6 V vs Ag/AgCl for 1.5 h at
a
Reaction conditions: C1 (0.13 mM), 1 (20.0 mM), amine (0.2 M),
nBu4NClO4 (0.1 M), MeCN (10 mL), CF-cathode, Zn-plate anode,
undivided cell, applied potential was −0.6 V vs Ag/AgCl for 1.5 h at
room temperature in the air. The yield of the product was based on
the initial concentration of 1 using biphenyl as the internal standard.
Electrical charges passed per mol of each substrate were around 1.1 F/
mol.
b
room temperature in air. The yield of the product was based on the
initial concentration of 1 using biphenyl as the internal standard.
c
Electrical charge passed per mol of substrate was 1.1 F/mol.
Continuous bubbling of O2 through the reaction mixture.
d
Without the cobalt complex (C1), the yield drastically
dropped to 17% (Table 1, entry 2). As expected, no product
(2a) was identified without an applied potential (Table 1,
entry 3). When the electrolysis was carried out over the
reduction potential of substrate 1 (−0.85 V vs Ag/AgCl in
MeCN, Figure S6), the yield decreased to 31% (Table 1, entry
4). Application of the imine/oxime-type cobalt complex
CoIII{(C2C3)(DO)(DOH)pn}Br2 (C2) (see section 2 in the
Supporting Information), showed a poor efficacy because of its
instability under the aerobic electrolysis conditions (Table 1,
entry 5). Conversely, when oxygen was continuously bubbled
through the reaction mixture, a competitive redox reaction
linear amines with the electronically diverse substituted group,
including alkyls (2a−2c), allyl (2d), phenyl (2h, 2i, 2l, 2m,
and 2w), isopropyl (2k), and benzyl group (2n, 2o, 2q−2t,
and 2x) were susceptible to this protocol with a moderate to
the high productivity of cyanoformamides formation. Linear
amines with the substituted cyclohexyl moiety had satisfactory
yields of 50% to 56% (2e, 2f).
Conversely, sterically hindered dicyclohexylamine gave a
lower yield of product (2g). Diphenylamine and N-phenyl-
benzylamine resulted in a low yield of the respective products
(2j and 2p) due to the steric hindrance by the bulky benzene
B
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Note
rings. The benzyl group with the substituted bulky group, such
as naphthalene (2u) and ethyl propionate (2v), were also
moderately compatible with the developed method.
We next examined the scope of the cyclic amines under the
optimized reaction conditions as shown in Scheme 3.
soquinoline, and tetrahydroquinoline, afforded moderate yields
of the products (3k, 3m, 3p, and 3q).
The electrochemical synthesis of cyanoformamides was
scaled up to gram as demonstrated by the synthesis of 3f
(Scheme 4 and Figure S5). The high yield of the product with
the 4.7 wt % of the C1 indicated the potential of the method
for cyanoformamides synthesis.
Scheme 3. Scope of Cyclic Amines for Cyanoformamides
a
Synthesis
Scheme 4. Grame-Scale Synthesis of 3f
To gain insight into the mechanistic details of this reductive
dehalogenation of 1, a series of experiments were carried out
with DFT calculations (Figure 1 and Scheme 5).21 First, the
Figure 1. Computed energy diagrams and optimized structures along
with the reaction pathways between the Co(I) species and 1 at the
TPSS level of theory. Units are in kcal/mol and angstrom.
a
Reaction conditions: C1 (0.13 mM), 1 (20.0 mM), amine (0.2 M),
Scheme 5. Mechanistic Studies
nBu4NClO4 (0.1 M), MeCN (10 mL), CF cathode, Zn-plate anode,
undivided cell, applied potential was −0.6 V vs Ag/AgCl for 1.5 h at
room temperature in air. The yield of the product was based on the
initial concentration of the 1 using biphenyl as the internal standard.
Electrical charge passed per mol of each substrate were around 1.1 F/
b
mol. At 45 °C.
Medicinally benign secondary cyclic amines such as piperidine
(3a), piperidines derivatives with the electronically diverse
functional group, such as CH3 (3b), CF3 (3c), CO2Me (3d),
dioxolane (3l), thiomorpholine (3e) morpholine (3f), and
morpholine derivative (3h), were proven to be very susceptible
to the protocol with robust yields of cyanoformamides.20
The seven- and eight-membered ring amines such as
azepane and azocane also produced the corresponding
products 3i and 3j in moderate yields, respectively.
Pyrrolidine-based polycyclic amines, indoline, and isoindoline
were well-amenable to the electrosynthesis to form 3n and 3o,
respectively. Additionally, piperidine-based polycyclic amines,
such as decahydroquinoline, tetrahydrothiophene, tertahydroi-
C
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formation of the alkylated complex has been checked. Ideally,
the Co(I) species of C1 formed an alkylated complex with an
organic halide,22 but the typical UV−vis spectrum for the
alkylated complex of C1 with 1 was not detected either
electrochemically or photochemically (Figures S8 and S9).
This then inspired us to investigate the transition state
energy profiles of 1 and the Co(I) state of C1 (Figure 1).
When the Co(I) catalyst was introduced into 1, a stabilized
reactant complex (RC) was formed by the interaction between
1 and the Co(I) species and allowed the radical intermediate
formation by the transition state (TSET) with the lower
activation energy than the transition state (TSSN2) to generate
the alkylated complex by an SN2 reaction. Therefore, the
reaction is kinetically controlled with the single electron
transfer, which is further approved by the energy diagram of
the molecular orbital (Figure S10) whereas, due to the strong
interaction between the Co(I) and 1, a stabilized energy level
was obtained that allows electron transfer from the HOMO of
the Co(I) species to the LUMO of the substrate 1.
Furthermore, an electrochemical reaction was carried out in
the presence of the radical scavenger, 5,5-dimethyl-1-pyrroline
N-oxide (DMPO), under a N2 atmosphere, and the reaction
mixture was analyzed by ESR to trap the spin adduct product
of the DMPO (Scheme 5a and see section 6d in the
Supporting Information). The ESR signal for the carbon-
centered radical trapped DMPO was g = 2.0056, AN = 14.01 G,
AH = 20.03 G. The hyperfine coupling constants were
consistent with those for the reported carbon-centered radical
trapped DMPO.23 When a similar ESR spin-trapping experi-
ment was conducted using DMPO under aerobic conditions in
order to capture the oxygen-centered radical, a complex ESR
spectrum was obtained (Figure S12).
This result suggested that a radical process is likely to be
involved, which was further strengthened by the controlled
reaction under air in the presence of the radical trapping
reagent DMPO that led to no product 2a (Scheme 5b).
Additionally, electrolysis under the N2 atmosphere (in the
glovebox, O2 < 1 ppm) led to the complete inhibition of
product 2a, which implied the crucial role of air or O2 to form
product 2a (Scheme 5c). Furthermore, a reaction under
isotopic oxygen (18O2) led to 3a′ as the major product
containing isotopic oxygen with the m/z 140.0 detected by the
GC−MS (Scheme 5d and see section 6f in the Supporting
Information), which implied that the source of the oxygen
atom in the product was O2 from the air.
Scheme 6. Proposed Reaction Mechanism
electrolysis (Figure S18). A total of 2.96 equiv moles of the
chloride ions was detected, which indicated the complete
removal of the Cl as a nontoxic chloride ion from substrate 1.
In conclusion, the B12 derivative-mediated dechlorination of
1 for the synthesis of cyanoformamides in the air at room
temperature has been demonstrated with a broad scope of
products. It is expected that the electrochemical technique
could be become one of the candidates for cyanoformamides
synthesis.
EXPERIMENTAL SECTION
■
General Information. The commercially available reagents were
purchased from Tokyo Kasei Kogyo (TCI), Sigma-Aldrich, Nacalai
Chemical, Wako, Shoko Co., Ltd., or others and used as received
unless otherwise noted. The solvents for the electrolysis were of
spectral grade and purchased from Wako. The B12 derived cobalt
complex (C1) was synthesized from cyanocobalamin (vitamin B12) by
a previously reported method.27 The cobalt complex CoIII{(C2C3)-
(DO)(DOH)pn}Br2 (C2) was prepared according to the literature
(for the structure of C2, see section 2 in the Supporting
Information).28 The UV−vis absorption spectra were measured by
1
a Hitachi U-3300 spectrophotometer at room temperature. The H,
13C, and 19F NMR spectra were recorded by a Bruker Avance NEO
400, Bruker Avance 500, and a Bruker Avance 300 spectrometer at the
Center of Advanced Instrumental Analysis of Kyushu University, and
1
the chemical shifts (δ) in the H NMR spectra are reported in parts
per million (ppm) relative to tetramethylsilane (TMS) (0.00 ppm) as
the internal standards in chloroform-d. The 1H NMR data are
reported as follows: chemical shift (δ), multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, p = pentet, se = sextet, dd
= doublet of doublets, dt = doublet of triplet, dq = doublet of quartet,
m = multiplet), coupling constant in Hertz (Hz) and number of
hydrogen atoms based on integration intensities. The 13C{1H} NMR
chemical shifts are reported in ppm relative to TMS (0.00 ppm) as the
internal standard in chloroform-d and coupling constant of J (C, F) in
Hz. The 19F NMR chemical shifts are reported in ppm relative to the
peak of C6F6 (−162.9 ppm) as the internal standard. The MALDI-
TOF mass spectra were obtained by an Autoflex III (Bruker
Daltonics) instrument under the linear/positive mode with dithranol
as the matrix. The high-resolution-mass spectra (EI and FAB) of the
products were obtained by a JEOL JMS-700instrumentt using m-
nitrobenzylalcohol as the matrix. The IR spectra were recorded by a
JASCO FT-IR 460 plus KH spectrophotometer using KBr disks and
NaCl crystals. The gas chromatography−mass spectra (GC−MS)
were obtained using a Shimadzu GCMS-QP5050A instrument
equipped with the Agilent J&W GC column, DB-1 (length of 30 m,
Based on the control experiments and from the previous
mechanistic understanding of the dechlorination of a
trichloromethylated compound in air,17 a mechanistic
hypothesis has been proposed as shown in Scheme 6.
Electrochemically generated active Co(I) species during the
electrolysis of 1 at −0.6 V vs Ag/AgCl led to the formation of
the dichloroacetonitrile carbon-centered radical (A), followed
by the radical anion intermediate [CCl3CN]•− generation with
the single electron transfer (SET) from Co(I). The carbon
centered-radical (A) may react with oxygen from the air to
form the peroxy radical (B).17,24 The coupling of B could
produce tetraoxide species (C) as the proposed intermediate,
and subsequent elimination of the oxygen and disproportio-
nation could form the cyanoformyl chloride (E).25 The
nucleophilic attack by the amine on the cynoformyl chloride
led to the desired product, cyanoformamides. Additionally, the
number of chloride ions was also spectrophotometrically
quantified using the mercury(II) thiocyanate method26 after
D
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ID of 0.25 mm, and film of 0.25 μm) and helium as the carrier gas.
For the measurement, the injector and detector temperatures were
250 °C, and the oven temperature was initially held at 100 °C for 2
min and then increased to 240 °C at a rate of 10 °C/min. The cyclic
voltammograms (CV) were obtained using a BAS CV 50W
electrochemical analyzer. A three-electrode cell equipped with a 3.0
mm diameter glassy carbon (GC) rod as the working electrode and a
1.6 mm diameter platinum coil as the counter electrodes, respectively,
was used. A Ag/AgCl (3.0 M NaCl) electrode served as the reference.
With the setup, the E1/2 value of the ferrocene−ferrocenium (Fc/Fc+)
was 0.44 V vs Ag/AgCl. The applied potential between the working
and reference electrodes for the electrolysis was kept constant using a
Hokuto DenkoHA BF-501A potentiostat. The ESR spectra were
measured using a Bruker EMX-Plus X-band spectrometer at room
temperature. The melting points of the compounds were measured by
a Yanaco Micro melting point apparatus, model MP-500P in degrees
Celsius (°C).
Dipropylcarbamoyl Cyanide (2b).15e This compound was purified
by column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a yellowish oil in (26.4 mg) 62% yield. 1H NMR
(500 MHz, CDCl3): δ 3.54−3.51 (t, J = 7.25 Hz, 2H), 3.35−3.32 (t, J
= 7.57 Hz, 2H), 1.73−1.66 (se, J = 7.25 Hz, 2H), 1.64−1.57 (se, J =
7.57 Hz, 2H), 1.0−0.97 (t, J = 7.25 Hz, 3H), 0.94−0.91 (t, J = 7.25
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.9, 110.9, 50.6,
∼
46.9, 22.0, 20.3, 11.2, 10.9. IR v : 2916, 2228, 1671, 1448, 1256
(
)
max
cm−1. GC−MS m/z: 154.
Dibutylcarbamoyl Cyanide (2c).15e This compound was purified
by column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a yellowish oil in (20.6 mg) 59% yield. 1H NMR
(500 MHz, CDCl3): δ 3.56−3.53 (t, J = 7.25 Hz, 2H), 3.38−3.35 (t, J
= 7.57 Hz, 2H), 1.66−1.60 (p, J = 7.57 Hz, 2H), 1.58−1.52 (p, J =
7.57 Hz, 2H), 1.42−1.36 (m, J = 7.57 Hz, 2H), 1.35−1.29 (m, J =
7.25 Hz, 2H), 1.00−0.97 (t, J = 7.25 Hz, 3H), 0.95−0.92 (t, J = 7.25
Hz, 3H). 13C{1H} NMR (125 MHz, CDCl∼3): δ 144.9, 110.9, 48.9,
General Procedure of Bulk Electrolysis. An oven-dried
cylinder-type undivided glass cell was equipped with a magnetic stir
45.2, 30.9, 29.1, 20.1, 19.8, 13.7, 13.6. IR v : 2960, 2228, 1675,
(
)
max
1429, 1218 cm−1. GC−MS m/z: 182.
n
bar, C1 (0.13 mM), Bu4NClO4 (0.1 M), diphenyl internal standard,
2-Allylpent-4-enoyl Cyanide (2d). This compound was purified by
column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a yellowish oil in (15.1 mg) 50% yield. 1H NMR
(500 MHz, CDCl3): δ 5.84−5.76 (m, 1H), 5.75−5.67 (m, 1H),
5.37−5.22 (m, 4H), 4.17−4.16 (d, J = 5.67 Hz, 2H), 4.02−4.01 (d, J
= 5.99 Hz, 2H). 13C{1H} NMR (1∼25 MHz, CDCl3): δ 144.8, 131.0,
and the substrate 1 dissolved in 10.0 mL of MeCN; then the amine
(0.2 M) was added. A CF cathode, a Zn plate anode, and the Ag/
AgCl (3 M, NaCl) reference electrode were placed in the glass cell
and connected to the potentiostat (Figure S4). The reaction mixture
was stirred. After electrolysis at −0.6 V vs Ag/AgCl for 1.5 h, a small
portion of the electrolyte solution was passed through a short column
packed with silica gel, and the reaction mixture was collected using an
ethyl acetate eluent and then analyzed by GC−MS to identify the
product. To get the pure product, the concentrated reaction mixture
was purified by column chromatography on silica gel with the eluent
of hexane/EtOAc (8:1 v/v).
130.3, 119.9, 110.5, 50.5, 47.1. IR v : 3086, 2231, 1676, 1416, 931
(
)
max
cm−1. GC−MS m/z: 150. HRMS (FAB) m/z: [M + H]+ calcd for
C8H11N2O+, 151.0871; found, 151.0875.
Cyclohexyl(methyl)carbamoyl Cyanide (2e). This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a white solid in (16.4 mg) 50% yield. Mp:
59.0−61.2 °C. 1H NMR (400 MHz, CDCl3, mixture of two rotamers)
(major): δ 4.06−3.98 (m, 1H), 2.90 (s, 3H), 1.92−1.68 (m, 5H),
1.62−1.52 (m, 1H), 1.49−1.32 (m, 3H), 1.18−1.06 (m, 1H);
(minor) δ 4.28−4.21 (m, 1H), 3.14 (s, 3H), 1.92−1.68 (m, 5H),
1.62−1.52 (m, 1H), 1.49−1.32 (m, 3H), 1.18−1.06 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3, mixture of two rotamers) (major):
δ 144.6, 110.7, 59.1, 30.9,∼29.3, 25.3; (minor) δ 144.8, 110.9, 53.9,
Gram-Scale Synthesis of 3f. An oven-dried 300 mL beaker was
equipped with a magnetic stir bar, C1 (50.0 mg, 0.14 mM),
nBu4NClO4 (10.99 g, 0.1 M), diphenyl internal standard (168.4 mg,
3.4 mM), and the substrate 1 (1.06 g, 23.0 mM) dissolved in 320.0
mL of MeCN; then the amine (0.2 M) was added. A CF cathode, a
Zn-plate anode, and the reference electrode Ag/AgCl (3 M, NaCl)
were placed in the glass beaker and connected to the potentiostat
(Figure S5). The reaction mixture was stirred. After electrolysis at
−0.6 V vs Ag/AgCl for 8.0 h, a small portion of the electrolyte
solution was passed through a short column packed with silica gel,
and the eluent was collected using ethyl acetate and injected into the
GC−MS to identify the desired product. The concentrated reaction
mixture was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) and isolated the product (3f) as a
white solid (0.83 g) with 81% yield.
DFT Calculations: Energy Diagrams and Optimized Structures
along with the Reaction Pathways between the Co(I) Species and
1 at the TPSS Level of Theory. Calculated energy diagrams and
optimized structures of reaction species were determined using the
TPSS functional29 combined with Grimme’s D3 correction.30,31 We
used the (14s9p5d)/[9s5p3d] primitive set of Wachters−Hay32,33
supplemented with one polarization function for the Co atom and
D95 (d,p)34 basis set for H, C, N, and Cl atoms. The open-shell
singlet state (OSS) and closed-shell singlet state (CSS) were used for
the optimization of TSET. OSS was computed by using the broken-
symmetry approach. Solvent effects were estimated for the methanol
by using the PCM method.35 The Gaussian 09 program36 was used
for all of the calculations.
31.2, 27.5, 25.2, 24.9. IR v : 2945, 2863, 2226, 1667, 1416, 1091
(
)
max
cm−1. GC−MS m/z: 186. HRMS (FAB) m/z: [M + H]+ calcd for
C9H15N2O+, 167.1184; found, 167.1196.
Cyclohexyl(ethyl)carbamoyl Cyanide (2f). This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a colorless oil in (27.8 mg) 56% yield. 1H
NMR (500 MHz, CDCl3, mixture of two rotamers) (major): δ 4.04−
3.98 (m, 1H), 3.39−3.35 (q, J = 7.25 Hz, 2H), 1.91−1.82 (m, 6H),
1.57−1.48 (m, 4H), 1.20−1.17 (t, J = 7.25 Hz, 3H); (minor) δ 4.11−
4.05 (m, 1H), 3.58−3.54 (q, J = 7.25 Hz, 2H), 1.77−1.67 (m, 4H),
1.46−1.36 (m, 6H), 1.36−1.34 (t, J = 7.25 Hz, 3H). 13C{1H} NMR
(125 MHz, CDCl3, mixture of two rotamers) (major): δ 144.5, 110.9,
59.7, 37.5, 31.9, 25.5, 25.0∼, 14.0; (minor) δ 145.0, 111.2, 55.7, 40.7,
30.4, 25.7, 25.2, 16.8. IR v : 2936, 2858, 2225, 2202, 1672, 1425
(
)
max
cm−1. GC−MS m/z: 180. HRMS (EI) m/z: [M]+ calcd for
C10H16N2O+, 180.1263; found, 180.1263.
Dicyclohexylcarbamoyl Cyanide (2g). This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a white solid in (9.6 mg) 21% yield. Mp:
111.2−112.6 °C. 1H NMR (500 MHz, CDCl3): δ 3.94 (br, 1H), 3.22
(br, 1H), 2.24−2.22 (m, 2H), 1.89−1.51 (m, 12H), 1.44−1.35 (m,
2H), 1.29−1.09 (m, 4H). 13C{1H} NMR (125 MHz, CDCl∼3): δ
Compounds 2a−2x and 3a−3p were synthesized as per the general
procedure of bulk electrolysis. Compound 3q was synthesized as per
the general procedure of bulk electrolysis at 45 °C.
Diethylcarbamoyl Cyanide (2a).15e This compound was purified
by column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a yellowish oil in (18.6 mg) 70% yield. 1H NMR
(400 MHz, CDCl3): δ 3.66−3.60 (q, J = 7.25 Hz, 2H), 3.48−3.42 (q,
J = 7.25 Hz, 2H), 1.33−1.30 (t, J = 7.25 Hz, 3H), 1.21−1.17 (t, J =
7.25 Hz, 3H). 13C{1H} N∼MR (100 MHz, CDCl3): δ 144.4, 110.8,
144.0, 111.5, 60.1, 56.7, 31.5, 29.1, 26.1, 25.6, 25.0, 24.9. IR v
:
)
(
max
2940, 2861, 2220, 1673, 1306, 996 cm−1. GC−MS m/z: 234. HRMS
(EI) m/z: [M]+ calcd for C14H22N2O+, 234.1732; found, 234.1736.
Methyl(phenyl)carbamoyl Cyanide (2h).15b This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as colorless solid in (18.0 mg) 49% yield.
43.7, 40.0, 14.5, 12.4. IR v : 2980, 2229, 1671, 1433, 1271 cm−1.
1
Mp: 78.9−82.3 °C. H NMR (400 MHz, CDCl3, mixture of two
(
)
max
GC−MS m/z: 126.
isomers) (major): δ 7.54−7.46 (m, 3H), 7.33−7.30 (m, 2H), 3.37 (s,
E
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Note
3H); (minor) δ 3.66 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
1395, 697 cm−1. GC−MS m/z: 189. HRMS (EI) m/z: [M]+ calcd for
C10H11N3O+, 189.0902; found, 189.0904.
mixture of two rotamers) (major): δ 144.6, 139.8, 130.2, 129.8, 127.0,
Benzyl(butyl)carbamoyl Cyanide (2o).7 This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a yellowish oil in (35.9 mg) 80% yield. 1H
NMR (500 MHz, CDCl3, mixture of two rotamers) (major): δ 7.43−
7.31 (m, 3H), 7.27−7.23 (m, 2H), 4.60 (s, 2H), 3.50−3.47 (t, J =
7.57 Hz, 2H), 1.64−1.58 (m, 2H), 1.39−1.32 (se, J = 7.57 Hz, 2H),
0.96−0.93 (t, J = 7.25 Hz, 3H); (minor) δ 7.43−7.31 (m, 3H), 7.27−
7.23 (m, 2H), 4.76 (s, 2H), 3.33−30.0 (t, J = 7.57 Hz, 2H), 1.53−
1.46 (m, 2H), 1.31−1.24 (se, J = 7.57 Hz, 2H), 0.91−0.88 (t, J = 7.25
Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3, mixture of two rotamers)
(major): δ 145.4, 134.8, 129.0, 128.4, 110.8, 48.1, 48.0, 30.4, 19.7,
∼
110.6, 36.8; (minor) δ 129.6, 128.3, 125.0, 39.3. IR v : 3355,
(
)
max
3067, 2230, 1686, 1388 cm−1. GC−MS m/z: 160.
Ethyl(phenyl)carbamoyl Cyanide (2i).15d This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as colorless crystalline solid in (14.5 mg)
1
46% yield. Mp: 47.8−49.5 °C. H NMR (500 MHz, CDCl3, mixture
of two rotamers) (major): δ 7.54−7.49 (m, 3H), 7.30−7.27 (m, 2H),
3.85−3.81 (q, J = 7.25 Hz, 2H), 1.20−1.17 (t, J = 7.25 Hz, 3H);
(minor) δ 7.48−7.37 (m, 3H), 7.22−7.20 (m, 2H), 4.07−4.03 (q, J =
7.25 Hz, 2H), 1.31−1.29 (t, J = 7.25 Hz, 3H). 13C{1H} NMR (125
MHz, CDCl3, mixture of two rotamers) (major): δ 144.4, 138.3,
13.5; (minor) δ 145.0, 134.3, 129.2, 128.8, 127.6, 110.9, 52.5, 44.7,
130.2, 129.9, 128.2, 110.7, 44.4, 12.4; (minor) δ 137.4, 129.7, 128.7,
∼
28.7, 20.0, 13.6. IR v : 2958, 2228, 1676, 1427, 725 cm−1. GC−
∼
(
)
max
126.5, 111.0, 47.4, 14.5. IR v : 2977, 2231, 1696, 1680, 1286
(
)
max
MS m/z: 216.
cm−1. GC−MS m/z: 174.
Benzyl(phenyl)carbamoyl Cyanide (2p).15d This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as yellowish liquid in (9.0 mg) 18% yield.
1H NMR (500 MHz, CDCl3, mixture of two rotamers) (major): δ
7.46−7.40 (m, 3H), 7.32−7.29 (m, 3H), 7.18−7.16 (m, 2H), 7.11−
7.06 (m, 2H), 4.91 (s, 2H); (minor) δ 5.14 (s, 2H). 13C{1H} NMR
Diphenylcarbamoyl Cyanide (2j).15d This compound was purified
by column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as white crystalline solid in (3.4 mg) 9% yield. Mp:
1
127.2−128.0 °C. H NMR (500 MHz, CDCl3): δ 7.55−7.51 (m,
3H), 7.41−7.38 (m, 4H), 7.31−7.28 (m, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 144.0, ∼139.5, 139.2, 130.3, 130.0, 129.4, 128.7,
(125 MHz, CDCl3): δ 144.9, 138.3, 134.7, 130.0, 130.0, 129.1, 128.8,
127.8, 125.1, 110.9. IR v : 3332, 3039, 2232, 1684,1512 cm−1.
∼
(
)
max
128.4, 128.4, 110.6, 53.1. IR v : 3066, 2229, 1682, 1493, 1396,
(
)
max
GC−MS m/z: 222.
697 cm−1. GC−MS m/z: 236. HRMS (EI) m/z: [M]+ calcd for
C15H12N2O+, 236.0950; found, 236.0951.
Ethyl(isopropyl)carbamoyl Cyanide (2k). This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a colorless oil in (15.8 mg) 54% yield. 1H
NMR (500 MHz, CDCl3, mixture of two rotamers) (major): δ 4.53−
4.47 (m, 1H), 3.37−3.32 (q, J = 7.25 Hz, 2H), 1.32−1.31 (d, J = 6.62
Hz, 6H), 1.22−1.20 (t, J = 7.25 Hz, 3H); (minor) δ 4.46−4.41 (m,
1H), 3.58−3.54 (q, J = 7.25 Hz, 2H), 1.37−1.34 (t, 3H), 1.26−1.25
(d, J = 6.94 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3, mixture of
Dibenzylcarbamoyl Cyanide (2q).15d This compound was purified
by column chromatography on silica gel with the eluent of hexane/
1
EtOAc (8:1 v/v) as a colorless oil in (18.9 mg) 48% yield. H NMR
(500 MHz, CDCl3): δ 7.45−7.39 (m, 3H), 3.38−7.35 (m, 3H),
7.26−7.24 (m, 2H), 7.21−7.20 (m, 2H), 4.65 (s, 2H), 4.49 (s, 2H).
13C{1H} NMR (125 MHz, CDCl3): δ 145.3, 134.3, 133.8, 129.3,
∼
129.1, 128.9, 128.7, 128.5, 127.9, 110.8, 51.4, 47.1. IR v : 3032,
(
)
two rotamers) (major): δ 144.3, 110.9, 51.4, 36.5, 21.3, 13.9; (minor)
max
2932, 2229, 1681, 1426, 1220 cm−1. GC−MS m/z: 250.
∼
max
δ 144.9, 111.2, 47.7, 40.4, 20.0, 16.6. IR v : [M]+ calcd for
(
)
Benzyl(methyl)carbamoyl Cyanide (2r).15e This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a colorless oil in (16.4 mg) 50% yield. 1H
NMR (500 MHz, CDCl3, mixture of two rotamers) (major): δ 7.44−
7.33 (m, 3H), 7.27−7.24 (m, 2H), 4.60 (s, 2H), 3.17 (s, 3H);
(minor) δ 7.44−7.33 (m, 3H), 7.27−7.224 (m, 2H), 4.77 (s, 2H),
2.92 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3, mixture of two
rotamers) (major): δ 144.8, 133.8, 128.9, 128.5, 127.7, 110.6, 50.5,
C7H12N2O+, 140.0950; found, 140.0946.
Methyl(p-tolyl) carbamoyl Cyanide (2l).15d This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as white crystalline solid in (13.6 mg) 44%
yield. Mp: 83.8−85.4 °C. 1H NMR (400 MHz, CDCl3, mixture of two
rotamers) (major): δ 7.30−7.28 (m, 2H), 7.20−7.17 (m, 2H), 3.34
(s, 3H), 2.41 (s, 3H); (minor) δ 7.24−7.24 (m, 2H), 7.15−7.14 (m,
2H), 3.63 (s, 3H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
mixture of two rotamers) (major): δ 144.7, 140.1, 137.3, 130.8, 126.8,
35.4; (minor) δ 145.2, 134.3, 129.3, 129.1, 128.5, 110.8, 54.7, 32.2.
∼
max
IR v : 3030, 2930, 2230, 1673, 1405, 1115 cm−1. GC−MS m/z:
(
)
110.7, 36.8, 21.2; (minor) δ 144.6, 138.4, 136.6, 130.2, 124.7. 110.9,
∼
174.
39.4, 21.1. IR v : 3332, 3039, 2232, 1684, 1512 cm−1. GC−MS
(4-Methoxybenzyl)(methyl)carbamoyl Cyanide (2s).15e This
compound was purified by column chromatography on silica gel
with the eluent of hexane/EtOAc (8:1 v/v) as a colorless oil in (31.0
mg) 77% yield. 1H NMR (500 MHz, CDCl3, mixture of two
rotomers) (major): δ 6.94−6.87 (m, 4H), 4.70 (s, 2H), 3.83 (s, 3H),
2.90 (s, 3H); (minor) δ 7.21−7.18 (m, 4H), 4.53 (s, 2H), 3.81 (s,
3H), 3.15 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3, mixture of two
rotamers) (major): δ 160.1, 145.1, 129.2, 125.8, 114.7, 110.8, 55.4,
(
)
max
m/z: 174.
(4-Chlorophenyl) (methyl)carbamoyl Cyanide (2m).15d This
compound was purified by column chromatography on silica gel
with the eluent of hexane/EtOAc (8:1 v/v) as a white solid in (7.0
1
mg) 21% yield. Mp: 46.7−48.1 °C. H NMR (500 MHz, CDCl3,
mixture of two rotamers) (major): δ 7.50−7.47 (m, 2H), 7.28−7.25
(m, 2H), 3.35 (s, 3H); (minor) δ 7.44−7.41 (m, 2H), 7.25−7.23 (m,
2H), 3.65 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3, mixture of two
54.2, 32.0; (minor) δ 159.8, 144.7, 130.0, 126.3, 114.5, 110.6, 55.4,
rotamers) (major): δ 144.4, 138.4, 136.0, 130.5, 128.4, 110.4, 36.8;
∼
49.9, 35.2. IR v : 2838, 2230, 1673, 1513, 1246 cm−1. GC−MS
∼
max
(
)
max
(minor) δ 137.7, 134.0, 129.8, 126.3, 39.1. IR v : 2235, 1692,
(
)
m/z: 204.
1492, 841 cm−1. GC−MS m/z: 194.
(4-Fluorobenzyl)(methyl)carbamoyl Cyanide (2t).15e This com-
pound was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) as a white solid in (29.0 mg) 80%
yield. Mp: 63.9−65.3 °C. 1H NMR (500 MHz, CDCl3, mixture of two
isomers) (major): δ 7.27−7.22 (m, 2H), 7.13−7.04 (m, 2H), 4.56 (s,
2H), 3.18 (s, 3H); (minor) δ 7.27−7.22 (m, 2H), 7.13−7.04 (m,
2H), 4.74 (s, 2H), 2.91 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3,
(3-Aminobenzyl)(methyl)carbamoyl Cyanide (2n). This com-
pound was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) as yollowish viscous liquid (27.4
mg) in 67% yield. 1H NMR (500 MHz, CDCl3, mixture of two
rotamers) (major): δ 7.19−7.12 (m, 1H), 6.68−6.60 (m, 2H), 6.56−
6.53 (m, 1H), 4.66 (s, 2H), 3.76 (br, 2H), 2.92 (s, 3H); (minor) δ
7.19−7.12 (m, 1H), 6.68−6.60 (m, 2H), 6.56−6.53 (m, 1H), 4.49 (s,
2H), 3.72 (br, 2H), 2.17 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3,
mixture of two rotamers) (major): δ 147.3, 145.2, 135.0, 130.2, 117.7,
1
mixture of two rotamers) (major): δ 164.0 (d, C−F, JC−F = 248.4
3
3
Hz), 145.2, 130.4 (d, C−F, JC−F = 8.3 Hz), 129.6 (d, C−F, JC−F
=
8.3 Hz), 116.2 (d, C−F, 2JC−F = 21.1 Hz), 110.4, 49.8, 35.4; (minor)
δ 161.8 (d, C−F, 1JC−F = 248.4 Hz), 144.7, 130.1 (d, C−F, 3JC−F = 8.3
115.4, 114.7, 110.8, 54.7, 32.2; (minor) δ 147.2, 144.9, 135.4, 130.0,
∼
max
3
2
118.6, 115.2, 113.7, 110.6, 50.5, 35.4. IR v : 3094, 2229, 1677,
Hz), 129.6 (d, C−F, JC−F = 8.3 Hz), 116.3 (d, C−F, JC−F = 21.1
(
)
F
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Note
Hz), 110.7, 54.0, 32.1. 19F NMR (282 MHz, CDCl3, mixture of two
(m, 2H), 1.37−1.36 (d, J = 6.94 Hz, 3H), 1.24, 1.22 (d, J = 7.25 Hz,
3H). 13C{1H} NMR (125 MHz, CDCl3): δ 143.5, 143.4, 110.7, 110.6,
51.3,∼45.7, 43.1, 37.7, 30.7, 29.5, 26.1, 25.0, 18.7, 18.7, 17.4, 15.6.
∼
isomers) (major): −114.11; (minor) −113.59. IR v : 3070, 2235,
(
)
max
1669, 1510, 1221, 835 cm−1. GC−MS m/z: 192.
Benzyl(naphthalen-2-yl)carbamoyl Cyanide (2u). This com-
pound was purified by column chromatography on silica gel with
the eluent of hexane/EtOAc (8:1 v/v) as yellowish solid in (21.8 mg)
34% yield. Mp: 98.7−100.2 °C. 1H NMR (500 MHz, CDCl3, mixture
of two rotamers), (major): δ 7.90−7.87 (t, J = 8.20 Hz, 2H), 7.82−
7.79 (m, 1H), 7.59−7.53 (m, 3H), 7.34−7.29 (m, 3H), 7.20−7.16
(m, 3H), 5.00 (s, 2H); (minor) δ 5.25 (s, 2H). 13C{1H} NMR (125
IR v : 2945, 2226, 1667, 1429 cm−1. GC−MS m/z: 152.
(
)
max
4-(Trifluoromethyl) piperidine-1-carbonyl Cyanide (3c). This
compound was purified by column chromatography on silica gel
with the eluent of hexane/EtOAc (8:1 v/v) as white crystalline solid
1
in (51.7 mg) 94% yield. Mp: 54.8−56.2 °C. H NMR (500 MHz,
CDCl3): δ 4.58−4.56 (d, J = 13.56 Hz, 1H), 4.37−4.35 (d, J = 13.87
Hz, 1H), 3.31−3.25 (td, J = 13.24, 3.15 Hz, 1H), 2.83−2.77 (td, J =
13.24, 3.15 Hz, 1H), 2.42−2.31 (m, 1H), 2.12−2.08 (dt, J = 13.56,
2.52 Hz, 1H), 2.05−2.01 (dt, J = 13.56, 2.52 Hz, 1H), 1.70−1.61 (dq,
MHz, CDCl3): δ 145.0, 135.6, 134.7, 133.4, 133.3, 130.4, 129.1,
∼
max
128.9, 128.5, 128.3, 128.0, 127.7, 127.3, 124.9, 110.7, 53.2. IR v
:
)
(
3056, 2232, 1680, 1398, 1280, 713 cm−1. GC−MS m/z: 286. HRMS
(EI) m/z: [M]+ calcd for C19H14N2O+, 286.1106; found, 286.1106.
Ethyl N-Benzyl-N-(cyanocarbonyl)glycinate (2v). This compound
was purified by column chromatography on silica gel with the eluent
of hexane/EtOAc (8:1 v/v) as a colorless oil in (28.3 mg) 58% yield.
1H NMR (500 MHz, CDCl3, mixture of two rotamers), (major): δ
7.43−7.34 (m, 3H), 7.27−7.26 (m, 2H), 4.88 (s, 2H), 4.23−4.17 (m,
2H), 4.00 (s, 2H), 1.28−1.24 (m, 3H); (minor) δ 7.43−7.34 (m,
3H), 7.24−7.22 (m, 2H), 4.66 (s, 2H), 4.23−4.17 (m, 2H), 4.16 (s,
2H), 1.28−1.24 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3, mixture
of two rotamers) (major): δ 166.8, 145.3, 133.2, 129.3, 129.1, 128.1,
J = 12.61, 4.73 Hz, 1H), 1.61−1.52 (dq, J = 12.61, 4.73 Hz, 1H).
1
13C{1H} NMR (125 MHz, CDCl3): δ 143.3, 123.1 (q, C−F, JC−F
=
2
278.6 Hz), 110.1, 45.9, 40.9, 39.9 (q, C−F, JC−F = 28.4 Hz), 25.1−
3
3
25.1 (q, C−F, JC−F = 2.8 Hz), 23.9−23.8 (q, C−F, JC−F = 2.8 Hz).
19F NMR (282 MHz, CDCl3, mixture of two isomer) (major): δ
∼
max
−74.80; (minor) δ −74.83. IR v : 3332, 3039, 2232, 1684, 1512
(
)
cm−1. GC−MS m/z: 206. HRMS (EI) m/z: [M]+ calcd for
C8H9F3N2O+, 206.0667; found, 206.0672.
Methyl 1-(Cyanocarbonyl)piperidine-4-carboxylate (3d). This
compound was purified by column chromatography on silica gel
with the eluent of hexane/EtOAc (8:1 v/v) as a colorless oil in (35.2
mg) 86% yield. 1H NMR (500 MHz, CDCl3): δ 4.21−4.17 (dt, 1H),
4.16−4.11 (dt, 1H), 3.73 (s, 3H), 3.47−3.41 (td, 1H), 3.14−3.09 (td,
1H), 2.68−2.63 (m, 1H), 2.10−2.05 (m, 1H), 2.03−1.99 (m, 1H),
1.88−1.80 (m, 1H), 1.78−1.71 (m, 1H). 13C{1H} NMR (125 MHz,
110.4, 62.4, 53.4, 45.3, 14.1; (minor) δ 167.2, 145.9, 133.7, 129.1,
∼
128.9, 128.8, 110.2, 62.0, 49.6, 49.0, 14.0. IR v : 2983, 2231, 1748,
(
)
max
1432, 1199, 1020 cm−1. GC−MS m/z: 246. HRMS (EI) m/z: [M]+
calcd for C13H14N2O3 , 246.1004; found, 246.1005.
+
Benzyl(4-methoxyphenyl)carbamoyl Cyanide (2w). This com-
pound was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) as a colorless oil in (20.2 mg) 35%
yield. 1H NMR (500 MHz, CDCl3, mixture of two rotamers),
(major): δ 7.32−7.29 (m, 3H), 7.17−7.16 (m, 2H), 6.99−6.96 (m,
2H), 6.90−6.86 (m, 2H), 4.86 (s, 2H), 3.81 (s, 3H); (minor) δ 5.09
(s, 2H), 3.78 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 160.6,
CDCl3): δ 173.6, 143.3, 110.3, 52.1, 46.2, 41.3, 40.2, 28.3, 27.2.
∼
IR v : 2957, 2231, 1734, 1674, 1433 cm−1. GC−MS m/z: 195.
(
)
max
+
HRMS (EI) m/z: [M]+ calcd for C9H12N2O3 , 196.0848; found,
196.0847.
Thiomorpholine-4-carbonyl Cyanide (3e). This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a yellowish oil in (18.8 mg) 58% yield. 1H
NMR (500 MHz, CDCl3): δ 4.05−4.03 (m, 2H), 3.92−3.90 (m, 2H),
145.2, 134.8, 130.8, 129.7, 129.2, 128.8, 128.4, 115.1, 110.7, 55.5,
∼
53.2. IR v : 2936, 2839, 2230, 1678, 1511, 1252, 1024 cm−1. GC−
(
)
max
2.77−2.75 (m, 2H), 2.69−2.66 (m, 2H). 13C{1H} NMR (125 MHz,
+
MS m/z: 266. HRMS (EI) m/z: [M]+ calcd for C16H14N2O2 ,
∼
266.1055; found, 266.1053.
CDCl3): δ 143.5, 110.0, 49.8, 44.8, 28.3, 27.1. IR v : 2920, 2228,
(
)
max
1669, 1433, 952 cm−1. GC−MS m/z: 156. HRMS (EI) m/z: [M]+
calcd for C6H8N2OS+, 156.0357; found, 156.0362.
Benzyl(1-phenylethyl)carbamoyl Cyanide (2x). This compound
was purified by column chromatography on silica gel with the eluent
of hexane/EtOAc (8:1 v/v) as a yellowish oil in (21.6 mg) 36% yield.
1H NMR (500 MHz, CDCl3, mixture of two rotamers), (major): δ
7.41−7.30 (m, 10H), 5.70−5.64 (m, 1H), 4.4.74−4.71 (d, 1H),
4.04−4.01 (d, 1H), 1.59−1.57 (d, 3H); (minor) δ 7.24−7.21 (m,
6H), 7.13−7.11 (m, 2H), 7.05−7.03 (m, 2H), 5.70−5.64 (m, 1H),
4.80−4.77 (d, 1H), 4.38−4.35 (d, 1H), 1.41−1.39 (d, 3H). 13C{1H}
NMR (125 MHz, CDCl3, mixture of two rotamers) (major): δ 145.6,
137.5, 136.3, 129.1, 128.9, 128.8, 128.8, 128.6, 128.5, 128.3, 127.9,
Morpholine-4-carbonyl Cyanide (3f).15e This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a white solid in (22.8 mg) 83% yield. Mp:
1
49.2−51.8 °C. H NMR (400 MHz, CDCl3): δ 3.79 (s, 4H), 3.74−
3.71 (m, 2H), 3.68−3.65 (m, 2H). 13C{1H} NMR (100 MHz,
∼
max
CDCl3): δ 143.4, 110.0, 66.6, 66.0, 47.1, 42.7. IR v : 2971, 2232,
(
)
1673, 1448, 1247 cm−1. GC−MS m/z: 140.
3,5-Dimethylpiperidine-1-carbonyl Cyanide (3g). This compound
was purified by column chromatography on silica gel with the eluent
of hexane/EtOAc (8:1 v/v) as a colorless oil in (20.0 mg) 59% yield.
1H NMR (500 MHz, CDCl3): δ 4.42−4.38 (dt, 1H), 4.14−4.11 (dt,
1H), 2.73−2.68 (t, 1H), 2.24−2.19 (t, 1H), 1.91−1.88 (m, 1H),
1.75−1.68 (m, 1H), 1.67−1.63 (m, 1H), 0.99−0.97 (d, J = 6.62 Hz,
3H), 0.92−0.83 (m, J = 6.62 Hz, 1H). 13C{1H} NMR (125 MHz,
127.8, 127.7, 127.4, 127.1, 111.0, 54.3, 46.0, 18.6; (minor) δ 145.9,
∼
137.9, 135.6, 111.1, 58.3, 49.9, 16.9. IR v : 3032, 2227, 1665,
(
)
max
1417, 697 cm−1. GC−MS m/z: 264. HRMS (FAB) m/z: [M + H]+
calcd for C17H17N2O+, 265.1341; found, 265.1328.
Piperidine-1-carbonyl Cyanide (3a).15b This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as a yellowish oil in (13.2 mg) 71% yield. 1H
NMR (500 MHz, CDCl3): δ 3.72−3.70 (t, J = 5.67 Hz, 2H), 3.60−
3.57 (t, J = 5.67 Hz, 2H), 1.75−1.68 (m, 4H), 1.64−1.60 (p, J = 5.67
CDCl3): δ 143.0, 110.6, 54.0, 48.9, 42.0, 32.4, 31.0, 18.8, 18.7.
∼
IR v : 2957, 2228, 1675, 1432, 1251 cm−1. GC−MS m/z: 166.
(
)
max
Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 143.3, 110.5, 48.2,
HRMS (EI) m/z: [M]+ calcd for C9H14N2O+, 166.1106; found,
166.1109.
∼
43.2, 26.4, 25.1, 24.1. IR v : 2980, 2229, 1671, 1448, 1256 cm−1.
GC−MS m/z: 138.
(
)
max
2,6-Dimethylmorpholine-4-carbonyl Cyanide (3h).15e This com-
pound was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) as colorless liquid in (26.4 mg)
2-Methylpiperidine-1-carbonyl Cyanide (3b).15e This compound
was purified by column chromatography on silica gel with the eluent
of hexane/EtOAc (8:1 v/v) as a white solid in (15.0 mg) 49% yield.
1
75% yield. H NMR (500 MHz, CDCl3): δ 4.31−4.27 (dt, J = 13.24
1
Hz, 2.1 Hz, 1H), 4.03−4.00 (dt, J = 13.24 Hz, 2.21 Hz, 1H), 3.67−
3.61 (m, 1H), 3.58−3.52 (m, 1H), 3.02− 2.97 (dd, J = 13.24 Hz,
10.72 Hz, 1H), 2.56−2.51 (dd, J = 13.24 Hz, 10.72 Hz, 1H), 1.27−
1.26 (d, J = 6.31 Hz, 3H), 1.24−1.23 (d, J = 6.31 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ 143.2, 110.2, 72.2, 71.5, 52.1, 47.6, 18.6,
Mp: 58.7−60.3 °C. H NMR (500 MHz, CDCl3): δ 4.77−4.74 (m,
1H), 4.56−4.54 (m, 1H), 4.34−4.30 (m, 1H), 4.08−4.04 (m, 1H),
3.36−3.30 (td, J = 13.24 Hz, 3.15 Hz, 1H), 2.87−2.81 (td, J = 13.56
Hz, 3.74 Hz, 1H), 1.86−1.79 (m, 2H), 1.77−1.74 (m, 2H), 1.73−
1.72 (m, 2H), 1.71−1.70 (m, 2H), 1.68−1.63 (m, 2H), 1.57−1.40
G
https://doi.org/10.1021/acs.joc.1c00837
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
∼
18.5. IR v : 2977, 2360, 2232, 1676, 1083 cm−1. GC−MS m/z:
Isoindoline-2-carbonyl Cyanide (3o). This compound was
purified by column chromatography on silica gel with the eluent of
hexane/EtOAc (8:1 v/v) as white crystalline solid in (16.7 mg) 55%
(
)
max
168.
Azepane-1-carbonyl Cyanide (3i). This compound was purified by
column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a colorless oil in (24.8 mg) 82% yield. H NMR
1
yield. Mp: 155.4−156.8 °C. H NMR (500 MHz, CDCl3): δ 7.38−
7.36 (m, 2H), 7.33−7.31 (m, 2H), 5.13 (s, 2H), 4.85 (s, 2H).
1
13C{1H} NMR (100 MHz, CDCl3): δ 143.1, 134.4, 133.9, 128.6,
(500 MHz, CDCl3): δ 3.75−3.73 (t, J = 5.99 Hz, 2H), 3.57−3.55 (t, J
∼
128.4, 123.1, 122.9, 110.9, 53.5, 52.1. IR v : 2870, 2232, 1678,
= 5.99 Hz, 2H), 1.87−1.83 (m, 2H), 1.80−1.75 (m, 2H), 1.62−1.59
(
)
max
1412 cm−1. GC−MS m/z: 172. HRMS (EI) m/z: [M]+ calcd for
C10H8N2O+, 172.0637; found, 172.0638.
(m, 4H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.0, 110.8, 49.1,
∼
max
46.1, 29.2, 27.2, 26.7, 26.5. IR v : 2931, 2228, 1671, 1429 cm−1.
(
)
3,4-Dihydroisoquinoline-2(1H)-carbonyl Cyanide (3p).15e This
compound was purified by column chromatography on silica gel with
the eluent of hexane/EtOAc (8:1 v/v) as a colorless oil in (25.3 mg)
GC−MS m/z: 152. HRMS (FAB) m/z: [M + H]+ calcd for
C8H13N2O+, 153.1028; found, 153.153.1027.
Azocane-1-carbonyl Cyanide (3j). This compound was purified by
column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a colorless oil in (18.7 mg) 58% yield. H NMR
1
71% yield. H NMR (500 MHz, CDCl3, mixture of two rotamers)
(major): δ 7.28−7.13 (m, 4H), 4.76 (s, 2H), 4.04−4.01 (t, J = 5.67
Hz, 2H), 3.04−3.01 (t, J = 5.99 Hz, 2H); (minor) δ 7.28−7.13 (m,
4H), 4.91 (s, 2H), 3.88−3.85 (t, J = 5.99 Hz, 2H), 2.96−2.93 (t, J =
5.99 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3, mixture of two
rotamers) (major): δ 144.0, 133.0, 130.5, 128.8, 127.4, 127.3, 126.6,
1
(500 MHz, CDCl3): δ 3.71−3.69 (t, J = 5.99 Hz, 2H), 3.53−3.51 (t, J
= 5.99 Hz, 2H), 1.90−1.85 (m, 2H), 1.81−1.77 (m, 2H), 1.67−1.63
(m, 2H), 1.57−1.53 (m, 4H). 13C{1H} NMR (125 MHz,∼CDCl3): δ
145.0, 110.9, 50.4, 47.1, 27.1, 26.5, 25.3, 25.2, 24.9. IR v : 2924,
(
)
max
110.5, 44.8, 44.5, 29.3; (minor) δ 143.7, 133.7, 130.6, 129.0, 127.8,
2227, 1668, 1423 cm−1. GC−MS m/z: 166. HRMS (EI) m/z: [M]+
∼
127.1, 126.2, 110.4, 48.3, 40.7, 27.8. IR v : 2905, 2229, 1671,
(
)
max
calcd for C9H14N2O+, 166.1106; found, 166.1103.
1446 cm−1. GC−MS m/z: 186. HRMS (EI) m/z: [M]+ calcd for
Octahydroquinoline-1(2H)-carbonyl Cyanide (3k). This com-
pound was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) as a colorless oil in (21.4 mg) 60%
yield. 1H NMR (500 MHz, CDCl3, mixture of two isomers) (major):
δ 3.78−3.73 (m, 1H), 3.68−3.62 (m, 1H), 3.31−3.26 (m, 1H), 2.26−
2.23 (m, 1H), 1.95−1.71 (m, 8H), 1.65−1.58 (m, 1H), 1.38−1.27
(m, 2H), 1.11−1.03 (m, 1H); (minor) δ 4.03−3.99 (m, 1H), 3.37−
3.32 (m, 1H), 3.21−3.16 (m, 1H), 2.18−2.16 (m, 1H), 1.49−1.40
(m, 6H), 1.26−1.12 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ
C11H10N2O+, 186.0793; found, 186.0795.
3,4-Dihydroquinoline-1(2H)-carbonyl Cyanide (3q). This com-
pound was purified by column chromatography on silica gel with the
eluent of hexane/EtOAc (8:1 v/v) as a yellowish oil in (22.0 mg) 48%
yield. 1H NMR (500 MHz, CDCl3, mixture of two isomers) (major):
δ 7.47−7.45 (d, J = 8.20 Hz, 1H), 7.33−7.29 (m, 2H), 7.26−7.23 (m,
1H), 3.87−3.85 (t, J = 6.62 Hz, 2H), 2.81−2.79 (t, J = 5.57 Hz, 2H),
2.05−2.00 (p, J = 6.62 Hz, 2H); (minor) δ 7.98−7.96 (d, J = 8.20 Hz,
1H), 7.25−7.21 (m, 1H), 7.20−7.16 (m, 2H), 4.09−4.07 (t, J = 5.57
Hz, 2H), 2.94−2.92 (t, J = 6.94 Hz, 2H), 2.17−2.12 (p, J = 6.62 Hz,
2H). 13C{1H} NMR (125 MHz, CDCl3, mixture of two rotamers)
(major): δ 143.7, 135.0, 129.5, 129.0, 127.8, 127.0, 123.3, 111.5, 43.6,
26.5, 23.2; (minor) δ 143.4,∼135.3, 133.4, 129.6, 126.6, 126.5, 123.7,
143.1, 111.0, 63.2, 43.7, 38.3, 32.8, 29.6, 26.9, 25.7, 25.4, 23.7.
∼
max
IR v : 2930, 2227, 1667, 1421 cm−1. GC−MS m/z: 192. HRMS
(
)
(EI) m/z: [M]+ calcd for C11H16N2O+, 192.1263; found, 192.1259.
1,4-Dioxa-8-azaspiro [4.5]decane-8-carbonyl Cyanide (3l). This
compound was purified by column chromatography on silica gel with
the eluent of hexane/EtOAc (8:1 v/v) as crystalline solid in (17.8
111.0, 47.6, 26.6, 23.4. IR v : 2953, 2227, 1677, 1656, 1492, 757
(
)
max
cm−1. GC−MS m/z: 186. HRMS (EI) m/z: [M]+ calcd for
1
C11H10N2O+, 186.0793; found, 186.0795.
mg) 53% yield. Mp: 59.3−61.5 °C. H NMR (500 MHz, CDCl3): δ
4.00 (s, 4H), 3.86−3.84 (t, J = 5.99 Hz, 2H), 3.74−3.71 (t, J = 5.99
Hz, 2H), 1.83−1.80 (t, J = 5.99 Hz, 2H), 1.75−1.73 (t, J = 5.99 Hz,
2H). 13C{1H} NMR (125 MH∼z, CDCl3): δ 143.2, 110.4, 106.2, 64.7,
ASSOCIATED CONTENT
* Supporting Information
■
sı
+
45.3, 40.2, 35.5, 34.3. IR v : [M]+ calcd for C9H12N2O3 ,
(
)
max
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00837.
196.0848; found, 196.0849.
6,7-Dihydrothieno[3,2-c]pyridine-5(4H)-carbonyl Cyanide (3m).
This compound was purified by column chromatography on silica gel
with the eluent of hexane/EtOAc (8:1 v/v) as a white solid in (32.6
Detail of the experimental procedure, electronic spectra,
products characterization data, and NMR spectra (PDF)
1
mg) 83% yield. Mp: 105.2−106.7 °C. H NMR (500 MHz, CDCl3,
mixture of two isomer) (major): δ 7.21−7.20 (d, J = 5.36 Hz, 1H),
6.81−6.80 (d, J = 5.36 Hz, 1H), 4.70 (s, 2H), 4.10−4.08 (t, J = 5.99
Hz, 2H), 3.06−3.04 (t, J = 5.67 Hz, 2H); (minor) δ 7.23−7.22 (d, J =
5.36 Hz, 1H), 6.84−6.83 (d, J = 5.36 Hz, 1H), 4.86 (s, 2H), 3.98−
3.95 (t, J = 5.99 Hz, 2H), 2.97−2.94 (t, J = 5.67 Hz, 2H). 13C{1H}
NMR (125 MHz, CDCl3, mixture of two rotamers) (major): δ 144.0,
132.0, 129.7, 124.7, 110.4, 45.2, 43.0, 25.6;∼(minor) δ 143.9, 133.3,
Accession Codes
The CCDC 2033642, 2033643, and 2033644 contain the
supplementary crystallographic data. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-
336033.
129.4, 124.3, 110.4, 47.1, 40.5, 24.3. IR v : 3121, 2915, 2229,
(
)
max
1680, 1433, 1236, 726 cm−1. GC−MS m/z: 192. HRMS (EI) m/z:
[M]+ calcd for C9H8N2OS+, 192.0357; found, 192.0356.
Indoline-1-carbonyl Cyanide (3n).15e This compound was purified
by column chromatography on silica gel with the eluent of hexane/
EtOAc (8:1 v/v) as a white solid in (11.1 mg) 32% yield. Mp: 98.9−
AUTHOR INFORMATION
Corresponding Authors
■
Yoshio Hisaeda − Department of Chemistry and Biochemistry,
Graduate School of Engineering, Kyushu University, Fukuoka
819-0395, Japan; orcid.org/0000-0001-9196-8006;
Email: yhisatcm@mail.cstm.kyushu-u.ac.jp
Hisashi Shimakoshi − Department of Chemistry and
Biochemistry, Graduate School of Engineering, Kyushu
University, Fukuoka 819-0395, Japan; orcid.org/0000-
0003-4644-2392; Email: shimakoshi@mail.cstm.kyushu-
u.ac.jp
1
100.7 °C. H NMR (500 MHz, CDCl3, mixture of two rotamers)
(major): δ 8.06−8.04 (d, J = 7.88 Hz, 1H), 7.28−7.25 (m, 2H),
7.21−7.16 (m, 1H), 4.42−4.38 (t, J = 7.88 Hz, 2H), 3.33−3.29 (t, J =
8.20 Hz, 2H); (minor) δ 7.93−7.91 (d, J = 8.20 Hz, 1H), 7.32−7.30
(m, 2H), 7.21−7.16 (m, 1H), 4.21−4.18 (t, J = 8.20 Hz, 2H), 3.19−
3.15 (t, J = 8.20 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3, mixture
of two rotamers) (major): δ 140.4, 132.6, 128.1, 126.7, 125.2, 117.9,
111.1, 49.3, 27.∼7; (minor) δ 140.7, 133.6, 127.9, 126.3, 126.2, 113.4,
48.4, 26.8. IR v : 2230, 1660, 1410, 764 cm−1. GC−MS m/z: 172.
(
)
max
H
https://doi.org/10.1021/acs.joc.1c00837
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(4) Nugent, J.; Schwartz, B. D. N-Methoxy-N-Methylcyanoforma-
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3834−3837.
Authors
Mohammad Moniruzzaman − Department of Chemistry and
Biochemistry, Graduate School of Engineering, Kyushu
University, Fukuoka 819-0395, Japan
Yoshio Yano − Department of Chemistry and Biochemistry,
Graduate School of Engineering, Kyushu University, Fukuoka
819-0395, Japan
Toshikazu Ono − Department of Chemistry and Biochemistry,
Graduate School of Engineering, Kyushu University, Fukuoka
819-0395, Japan; orcid.org/0000-0001-5427-8540
Kenji Imamura − Department of Chemistry and Biochemistry,
Graduate School of Engineering and Institute for Materials
Chemistry and Engineering, Kyushu University, Fukuoka
819-0395, Japan
Yoshihito Shiota − Institute for Materials Chemistry and
Engineering, Kyushu University, Fukuoka 819-0395, Japan;
orcid.org/0000-0003-2054-9845
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Kazunari Yoshizawa − Institute for Materials Chemistry and
Engineering, Kyushu University, Fukuoka 819-0395, Japan;
orcid.org/0000-0002-6279-9722
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00837
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was partially supported by a Grant-in-Aid for
Scientific Research (B) (JP19H02735) from the Japan Society
for the Promotion of Science (JSPS). Part of the study was
performed under the Cooperative Research Program of
“Network Joint Research Center for Materials and Devices:
Dynamic Alliance for Open Innovation Bridging Human,
Environment and Materials” (20214031).
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