Synthesis of 2-(Cyanomethyl)benzoic Esters via Carbon-Carbon Bond Cleavage of Indanones

Article abstract of DOI:10.1021/acs.joc.1c01131

A novel synthesis of 2-(cyanomethyl)benzoic esters from indanone derivatives has been established. This reaction proceeds via a deprotonation of alcohols with a chemical base, followed by a nucleophilic addition to indanones and Beckmann fragmentation. In addition, this reaction could also work under electrochemical conditions, and no external chemical bases were needed. This mild method offers a novel strategy for the late-stage functionalization of various natural alcohols.

Full text of DOI:10.1021/acs.joc.1c01131

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Synthesis of 2‑(Cyanomethyl)benzoic Esters via Carbon−Carbon
Bond Cleavage of Indanones
Xiangtai Meng, Dengfeng Chen, Rui Liu, Ping Jiang, and Shenlin Huang*
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ABSTRACT: A novel synthesis of 2-(cyanomethyl)benzoic esters
from indanone derivatives has been established. This reaction
proceeds via a deprotonation of alcohols with a chemical base,
followed by a nucleophilic addition to indanones and Beckmann
fragmentation. In addition, this reaction could also work under electrochemical conditions, and no external chemical bases were
needed. This mild method offers a novel strategy for the late-stage functionalization of various natural alcohols.
2-(Cyanomethyl)benzoic esters have become an important
class of building blocks in synthetic chemistry. As shown in
Figure 1, their synthetic applications were highlighted in the
Scheme 1. Synthesis of 2-(Cyanomethyl)benzoic Esters
variety of convenient methods.6 We envisaged to construct the
2-(cyanomethyl)benzoic esters from readily available indanone
oxime ester7 via a Beckmann fragmentation8 (Scheme 1d).
This working hypothesis could be potentially used for late-
stage functionalization of natural alcohols and indanones.
Herein, we report a novel synthesis of 2-(cyanomethyl)benzoic
esters via the fragmentation of indanone oxime esters either in
the presence of a chemical base or under electrochemical
conditions.
At the outset, we examined our hypothesis with ketoxime
ester 1a as the model substrate (Table 1). A range of
experiments identified the optimal reaction conditions (entry
1), which employed Et2NH as the base in ethanol at room
temperature. The use of other bases could also form the
desired product 3aa, albeit in lower yields (entries 2−7).
Raising the reaction temperature did not affect the reaction
efficiency (entry 8). The shorter reaction time delivered ethyl
2-(cyanomethyl)benzoate with a diminished yield (entry 9).
Figure 1. Synthetic utility of 2-(cyanomethyl)benzoic esters.
construction of various bioactive heterocycles1 including drug
candidates CWJ-a-5 and DCZ0359. A classical method for the
synthesis of 2-(cyanomethyl)benzoic esters is the SN2
nucleophilic substitution of benzyl halides with highly toxic
metal cyanides (Scheme 1a).2 In 2005, Kunai and co-workers
reported an alternative approach taking advantage of aryne
insertion into α-cyano esters (Scheme 1b).3 Lei developed an
efficient Ni-catalyzed coupling reaction of arylboronic esters
with α-bromonitriles in 2011 (Scheme 1c).4 Nevertheless, the
synthetic approaches to 2-(cyanomethyl)benzoic esters are still
underdeveloped.
Received: May 14, 2021
Published: July 27, 2021
Indanones are widely available feedstocks, as they are found
in various natural products5 and can be also be accessed via a
https://doi.org/10.1021/acs.joc.1c01131
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a
propanol, and butanol, were found to be suitable substrates for
this transformation, affording products 3aa−3ad in high yields.
Gratifyingly, the reaction is scalable. On 4 mmol scale, 3aa
could be obtained in 88% yield after 28 h. Both acyclic and
cyclic secondary alcohols, such as isopropanol, cyclopentanol,
and cyclohexanols, were proven to be effective reaction
partners as well, giving the desired products 3ae−3ai. Notably,
diols could be selectively converted to the corresponding
monoesters 3aj and 3ak in excellent yields. Alcohols possessing
ether (3al and 3am), alkene (3an), alkyne (3ao), benzyl
(3ap), furan (3aq), and tetrahydrofuran (3ar) groups all
worked very well.
To further demonstrate the applicability of this protocol, a
series of natural alcohols were subjected to the reaction
conditions. Cinnamyl alcohol and piperonol underwent the
fragmentation smoothly to deliver 3as and 3at in 65% and 87%
yield, respectively. Alcohols form plant essential oil, such as
citronellol (3au), tetrahydrogeraniol (3av), geraniol (3aw),
nerol (3ax), and perillyl alcohol (3ay), posed no problem
either. Abietyl alcohol (3az), from natural rosin, was
compatible with this fragmentation.
Table 1. Optimization of Reaction Conditions
b
entry
deviation from standard conditions
yield (%)
1
none
94
11
10
75
83
78
90
93
75
40
82
88
2
3
t-BuOK as base
KOH as base
4
5
NaOAc as base
K2CO3 as base
6
7
NaHCO3 as base
DBU as base
8
at 50 °C
9
reaction time 12 h
0.5 equiv Et2NH
EtOH/DCM (0.5 mL/0.5 mL)
EtOH/MeCN (0.5 mL/0.5 mL)
10
11
12
a
Reaction conditions: 1a (0.1 mmol), base (0.2 mmol, 2 equiv), and
EtOH (0.1 M). Yields were determined by HPLC analysis.
b
Next, we evaluated different protecting groups of oxime
esters. As shown in Figure 2, benzoate 1a′ worked even better
than p-trifluoromethylbenzoate 1a. Moreover, O-acetyl oxime
1a′′ reacted efficiently with ethanol, leading to 3aa in
comparable yield (93%). Therefore, O-acetyl oximes were
used for the further studies.
Two equivalents of Et2NH were found to be required to reach
full conversion (entry 10). The amount of ethanol could be
reduced when DCM or MeCN was used as the cosolvent
(entries 11 and 12), which would be beneficial to the
evaluation of alcohol scope.
The indanone substrate scope was also probed (Scheme 3).
Indanones bearing either one or two electron donating groups
(3ba−3da) all gave good yields. Besides, indanones containing
With the optimized conditions in hand, we evaluated the
generality of this fragmentation for a range of alcohols
(Scheme 2). Simple linear alcohols, such as methanol, ethanol,
a d
,
Scheme 2. Scope of Alcohols
a
b
Reaction conditions: 1 (0.1 mmol), alcohol (1.0 mL, 0.1 M), and Et2NH (0.2 mmol, 2.0 equiv). 1 (0.1 mmol), alcohol (0.1 mL), CH3CN (0.9
c
d
mL), and Et2NH (0.4 mmol, 4.0 equiv). 1 (0.1 mmol), alcohol (10.0 equiv), DCM (1.0 mL), and Et2NH (0.4 mmol, 4.0 equiv). Isolated yield.
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Scheme 4. Mechanistic Considerations
Figure 2. Evaluation of protecting groups.
a b
,
Scheme 3. Scope of Indanones
stoichiometric amounts of the chemical base Et2NH. In an
undivided electrolytic cell, the electrochemically initiated
fragmentation of 1a occurred efficiently under electrolysis at
room temperature for 8 h, when ethanol or methanol were
used as the solvent, two graphite plates as the electrodes, and
KI as the electrolyte (Scheme 4b). Thus, a plausible reaction
mechanism is proposed (Scheme 4c). Initially, intermediate A
was produced by the addition of alcohol 2 to the activated
ketone 1. Subsequently, a Beckmann fragmentation was
promoted by either Et2NH or electrogenerated base RO−,
furnishing the final product 3. In the electrochemical process,
ketone 1 could be also attacked by alkoxide anion RO−, which
was generated by cathodic reduction of alcohol 2.
In conclusion, we have developed a facile synthesis of 2-
(cyanomethyl)benzoic esters from readily available indanones.
This reaction is initiated by the generation of alkoxide anion
via deprotonation or cathodic reduction, followed by
nucleophilic addition and Beckmann fragmentation. Moreover,
this transformation not only unlocks the new reactivity of
indanones but also offers a novel method for the late-stage
functionalization of various natural alcohols.
a
Reaction conditions: 1 (0.1 mmol), EtOH (1.0 mL, 0.1 M), and
b
Et2NH (0.2 mmol, 2.0 equiv). Isolated yield.
halide substituents, which provide opportunities for further
functionalization, still provided the desired 2-(cyanomethyl)-
benzoic esters 3ea−3ha in high yields. In addition, indanones
bearing electron-withdrawing groups CF3 (3ia) and CN (3ja)
proved to be competent substrates. Moreover, complex β-
cholestanol derivative afforded the desired ester in 41% yield.
Substituents at the aliphatic position of indanone derivatives
were also explored. For example, O-acetyl oxime 1l exhibited
high reactivity, yielding the corresponding 2-(cyanomethyl)-
benzoic ester 3la in 85% yield. Finally, benzosuberone
derivative 1m smoothly participated in this fragmentation,
producing 3ma in 62% yield.
To investigate the pathway for this transformation, we
conducted several control experiments (Scheme 4). First, the
addition of common free radical scavengers such as TEMPO,
BHT, and 1.1-diphenylethylene (see the Supporting Informa-
tion) had little effect on the reaction (Scheme 4a), which ruled
out the well-known radical pathway of oxime esters.9 As
organic electrochemistry has become one of the highly
sustainable techniques in recent years,10 we also tested the
possibility to generate nucleophilic reagents (alkoxide anions)
under electrochemical conditions,11 avoiding the use of
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all glassware was
oven-dried. All solvents were distilled from appropriate drying agents
prior to use. All reagents were used as received from commercial
suppliers unless otherwise indicated. The instrument for electrolysis is
a domestic dual display DC stabilized power supply (UTP1303/
UTP3305). Both anode electrode and cathode electrode are graphite
plates (1.0 cm × 1.0 cm × 0.2 cm). Reactions were monitored using
thin layer chromatography (TLC) carried out on Merck silica gel
plates (60F-254) using UV light as the visualizing agent and high
performance liquid chromatography (HPLC) with UV detection at
254 nm. For HPLC yields, UV response factors relative to an internal
standard (1-nitronaphthalene). Flash column chromatography was
performed using silica gel 60 (200−300 mesh). HRMS data were
recorded on ThermoFisher LTQ Orbitrap XL or Agilent 6500
1
QTOFMS-ESI. All H NMR, 13C NMR spectra were recorded on
Bruker DRX600 and AMX-400 instruments. Chemical shifts were
given in parts per million (ppm, δ), referenced to the solvent peak of
CDCl3, defined at δ = 7.26 (1H NMR), defined at δ = 77.16 (13C
NMR). Coupling constants were quoted in Hz (J). 1H NMR
spectroscopy splitting patterns were designated as singlet (s), doublet
(d), triplet (t), quartet (q). Splitting patterns that could not be
interpreted or easily visualized were designated as multiplet (m) or
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1
broad (br). The diastereomeric ratios were determined by H NMR
analysis.
2.34 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 188.0, 168.8,
160.1, 159.9, 139.2, 138.6, 127.6, 126.4, 106.1, 55.8, 29.1, 19.7.
HRMS-ESI (m/z) [M + Na]+ calculated for C12H11NNaO4 256.0580,
found 256.0583.
General Procedure for Preparation of Oxime Esters. A
solution of 1-indanone12 S1 (5 mmol) in MeOH (5 mL) was slowly
added to isoamyl nitrite (1.06 mL, 7.5 mmol) at room temperature.
The reaction mixture was heated to 40 °C (in an oil bath). Then,
concentrated HCl (0.25 mL) was slowly added to the mixture and the
mixture was stirred for 2 h. The reaction mixture was cooled to room
temperature and a white precipitate formed. Half of methanol was
removed by rotary evaporation before filtration. The crude solid was
washed with dichloromethane three times, and dried under a vacuum
to afford oxime S2.
2-(Acetoxyimino)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
(1d). 1d was prepared from the corresponding 1-indanone (5.0
mmol) as white solid (771.0 mg, 59%). (Rf = 0.2, petroleum ether/
1
ethyl acetate = 8/2). H NMR (600 MHz, CDCl3) δ 7.28 (s, 1H),
6.89 (s, 1H), 4.00 (s, 3H), 3.91 (s, 3H), 3.83 (s, 2H), 2.34 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 186.2, 169.2, 159.8, 157.3,
150.2, 142.2, 131.0, 107.4, 105.3, 56.6, 56.3, 29.4, 19.7. HRMS-ESI
(m/z) [M + Na]+ calculated for C13H13NNaO5 286.0686, found
286.0695.
2-(Acetoxyimino)-5-chloro-2,3-dihydro-1H-inden-1-one (1e). 1e
was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (446.9 mg, 38%). (Rf = 0.2, petroleum ether/ethyl acetate
= 8/2). 1H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 1H), 7.52
(s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 3.94 (s, 2H), 2.34 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 186.6, 168.6, 158.6, 147.6, 143.4, 135.8,
129.5, 127.1, 126.2, 29.6, 19.6. HRMS-ESI (m/z) [M + Na]+
calculated for C11H8ClNNaO3 260.0085, found 260.0088.
2-(Acetoxyimino)-6-bromo-2,3-dihydro-1H-inden-1-one (1f). 1f
was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (751.2 mg, 53%). (Rf = 0.2, petroleum ether/ethyl acetate
= 8/2). 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 1.8 Hz, 1H), 7.81
(dd, J = 8.1, 1.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 3.91 (s, 2H), 2.36
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 186.7, 168.7, 158.6,
144.7, 139.6, 138.9, 128.4, 128.0, 123.0, 29.5, 19.7. HRMS-ESI (m/z)
[M + Na]+ calculated for C11H8BrNNaO3 303.9579, found 303.9584.
2-(Acetoxyimino)-5-bromo-2,3-dihydro-1H-inden-1-one (1g). 1g
was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (789.6 mg, 56%). (Rf = 0.2, petroleum ether/ethyl acetate
= 8/2). 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.71
(s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 3.95 (s, 2H), 2.35 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 186.8, 168.6, 158.5, 147.6, 136.2, 132.4,
132.3, 130.1, 126.2, 29.5, 19.7. HRMS-ESI (m/z) [M + Na]+
calculated for C11H8BrNNaO3 303.9579, found 303.9584.
In the second step, oxime S2 was acylated by dissolving in dried
CH2Cl2 (4.5 mL, 4.5 mmol, 1.0 mL per mmol), followed by the
addition of triethylamine (0.943 mL, 6.75 mmol, 1.5 equiv) and acyl
chlorides (6.75 mmol, 1.5 equiv) at −10 °C. After 4 h, the reaction
was quenched with saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers
were dried over Na2SO4. The combined organic layers were
concentrated in vacuo and the residue was purified by recrystallization
with petroleum ether and ethyl acetate to afford the desired product
1.
2-(((4-(Trifluoromethyl)benzoyl)oxy)imino)-2,3-dihydro-1H-
inden-1-one (1a). 1a was prepared from the corresponding 1-
indanone (5.0 mmol) as white solid (1416.3 mg, 85%). (Rf = 0.2,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
8.23 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz,
2H), 7.73 (t, J = 7.4 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.5
Hz, 1H), 4.13 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 187.5,
161.8, 161.0, 145.9, 137.4, 137.1, 135.3 (q, J = 33.0 Hz), 131.4, 130.3,
128.8, 126.8, 125.8 (q, J = 3.7 Hz), 125.2, 123.4 (q, J = 272.9 Hz),
29.9. HRMS-ESI (m/z) [M + Na]+ calculated for C17H10F3NNaO3
356.0505, found 356.0510.
2-(Acetoxyimino)-4-bromo-2,3-dihydro-1H-inden-1-one (1h). 1h
was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (477.9 mg, 34%). (Rf = 0.2, petroleum ether/ethyl acetate
= 8/2). 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 7.9 Hz, 1H), 7.83
(d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 3.86 (s, 2H), 2.35 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 187.4, 168.4, 158.3, 146.5,
139.4, 139.1, 130.3, 123.7, 122.1, 31.1, 19.6. HRMS-ESI (m/z) [M +
Na]+ calculated for C11H8BrNNaO3 303.9579, found 303.9585.
2-(Acetoxyimino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-
one (1i). 1i was prepared from the corresponding 1-indanone (5.0
mmol) as white solid (650 mg, 48%). (Rf = 0.2, petroleum ether/ethyl
2-((Benzoyloxy)imino)-2,3-dihydro-1H-inden-1-one (1a′). 1a′
was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (1206.6 mg, 90%). (Rf = 0.2, petroleum ether/ethyl
1
acetate = 8/2). H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.4 Hz,
2H), 7.90 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.4
Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.52−7.48 (m, 2H), 7.47 (d, J =
7.4 Hz, 1H). 4.10 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ
187.7, 162.9, 160.5, 146.1, 137.5, 136.9, 134.0, 129.9, 128.8, 128.7,
128.1, 126.8, 125.1, 29.9. HRMS-ESI (m/z) [M + Na]+ calculated for
C16H11NNaO3 288.0631, found 288.0637.
2-(Acetoxyimino)-2,3-dihydro-1H-inden-1-one (1a′′). 1a′′ was
prepared from the corresponding 1-indanone (5.0 mmol) as white
solid (843.2 mg, 81%). (Rf = 0.2, petroleum ether/ethyl acetate = 8/
2). 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 7.7 Hz, 1H), 7.71 (t, J
= 7.5 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 3.96
(s, 2H), 2.34 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 188.0,
168.7, 159.3, 146.3, 137.3, 136.9, 128.6, 126.9, 15.0, 29.8, 19.6.
HRMS-ESI (m/z) [M + Na]+ calculated for C11H9NNaO3 226.0474,
found 226.0475.
1
acetate = 8/2). H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 7.7 Hz,
1H), 7.97 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 4.12 (s, 2H),
2.36 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 186.7, 168.3,
157.6, 143.5, 138.5, 133.2 (q, J = 4.5 Hz), 129.1, 128.7 (q, J = 32.8
Hz), 128.3, 123.4 (q, J = 273.4 Hz), 29.9 (q, J = 1.4 Hz), 19.6.
HRMS-ESI (m/z) [M + Na]+ calculated for C12H8F3NNaO3
294.0348, found 294.0347.
2-(Acetoxyimino)-1-oxo-2,3-dihydro-1H-indene-4-carbonitrile
(1j). 1j was prepared from the corresponding 1-indanone (5.0 mmol)
as white solid (193.0 mg, 17%). (Rf = 0.2, petroleum ether/ethyl
2-(Acetoxyimino)-6-methyl-2,3-dihydro-1H-inden-1-one (1b). 1b
was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (694 mg, 32%). (Rf = 0.2, petroleum ether/ethyl acetate =
1
acetate = 8/2). H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 7.7 Hz,
1H), 8.01 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 4.15 (s, 2H),
2.37 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 186.1, 167.8,
157.1, 149.2, 139.3, 138.2, 129.5, 129.1, 115.4, 111.9, 29.5, 19.5.
HRMS-ESI (m/z) [M + Na]+ calculated for C12H8N2NaO3 251.0427,
found 251.0425.
1
8/2). H NMR (600 MHz, CDCl3) δ 7.62 (s, 1H), 7.48 (d, J = 7.8
Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 3.86 (s, 2H), 2.38 (s, 3H), 2.30 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 188.0, 168.7, 159.8, 143.7,
138.7, 138.1, 137.4, 126.5, 124.8, 29.5, 21.1, 19.6. HRMS-ESI (m/z)
[M + Na]+ calculated for C12H11NNaO3 240.0631, found 240.0633.
2-(Acetoxyimino)-6-methoxy-2,3-dihydro-1H-inden-1-one (1c).
1c was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (481.2 mg, 41%). (Rf = 0.2, petroleum ether/ethyl acetate
= 8/2). 1H NMR (600 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 1H), 7.32
(s, 1H), 7.28 (dd, J = 8.4, 2.5 Hz, 1H), 3.88 (s, 2H), 3.85 (s, 3H),
2-(Acetoxyimino)-5-(((3R,5S,8R,9S,10S,13R,14S,17R)-10,13-di-
methyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1H-
cyclopenta[a]phenanthren-3-yl)oxy)-2,3-dihydro-1H-inden-1-one
(1k). 1k was prepared from the corresponding 1-indanone (5.0 mmol)
as white solid (1234.0 mg, 42%). (Rf = 0.2, petroleum ether/ethyl
1
acetate = 8/2). H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz,
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1H), 6.91 (d, J = 8.7 Hz, 1H), 6.87 (s, 1H), 4.67 (s, 1H), 3.84 (s,
2H), 2.30 (s, 3H), 1.94 (d, J = 12.6 Hz, 1H), 1.87 (d, J = 14.4 Hz,
1H), 1.82−1.68 (m, 2H), 1.66−1.42 (m, 8H), 1.37−1.26 (m, 5H),
1.25−1.14 (m, 4H), 1.13−1.03 (m, 5H), 1.01−0.91 (m, 3H), 0.87 (d,
J = 6.5 Hz, 3H), 0.83 (dd, J = 6.6, 2.7 Hz, 6H), 0.81 (s, 3H), 0.74 (td,
J = 12.3, 3.8 Hz, 1H), 0.62 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 185.7, 169.0, 165.5, 160.0, 149.4, 130.5, 127.1, 117.4, 111.5,
73.4, 56.5, 56.3, 54.1, 42.6, 40.0, 39.6, 39.5, 36.2, 35.8, 35.8, 35.5,
32.6, 32.5, 31.9, 29.9, 28.4, 28.2, 28.0, 25.7, 24.2, 23.7, 22.8, 22.6,
20.8, 19.7, 18.7, 12.1, 11.4. HRMS-ESI (m/z) [M + Na]+ calculated
for C38H55NNaO4 612.4023, found 612.4027.
2-(Acetoxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (1l).
1l was prepared from the corresponding 1-indanone (5.0 mmol) as
white solid (924.1 mg, 80%). (Rf = 0.2, petroleum ether/ethyl acetate
= 8/2). 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.74
(t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H),
2.37 (s, 3H), 1.68 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ
187.8, 168.5, 164.4, 158.3, 137.2, 134.9, 128.6, 124.5, 123.6, 43.2,
25.6, 19.6. HRMS-ESI (m/z) [M + Na]+ calculated for
C13H13NNaO3 254.0787, found 254.0792.
Procedure A. Diethylamine (0.2 mmol, 2.0 equiv) was added to a
solution of oxime ester 1a (0.1 mmol, 1.0 equiv) in alcohol 2 (1.0 mL,
0.1 M) at room temperature. After 24 h, TLC indicated complete
conversion of the starting material and the solvent was removed with
a rotary evaporator. The pure product was obtained by flash
chromatography on silica gel using petroleum ether and ethyl acetate
as the eluent.
Procedure B. Diethylamine (0.4 mmol, 4.0 equiv) was added to a
solution of oxime ester 1a (0.1 mmol, 1.0 equiv) in alcohol 2 (0.1
mL) and CH3CN (0.9 mL) at room temperature. After 24 h, TLC
indicated complete conversion of the starting material and the solvent
was removed with a rotary evaporator. The pure product was obtained
by flash chromatography on silica gel using petroleum ether and ethyl
acetate as the eluent.
Procedure C. Diethylamine (0.4 mmol, 4.0 equiv) was added to a
solution of oxime ester 1a (0.1 mmol, 1.0 equiv) and alcohol 2 (10.0
equiv) in DCM (1.0 mL) at room temperature. After 24 h, TLC
indicated complete conversion of the starting material and the solvent
was removed with a rotary evaporator. The pure product was obtained
by flash chromatography on silica gel using petroleum ether and ethyl
acetate as the eluent.
Procedure D. Diethylamine (0.2 mmol, 2.0 equiv) was added to a
solution of oxime ester 1 (0.1 mmol, 1.0 equiv) in ethanol (1.0 mL,
0.1 M) at room temperature. After 24 h, TLC indicated complete
conversion of the starting material and the solvent was removed with
a rotary evaporator. The pure product was obtained by flash
chromatography on silica gel using petroleum ether and ethyl acetate
as the eluent.
Ethyl 2-(cyanomethyl)benzoate (3aa). Following General Proce-
dure A: Colorless oil, 17.0 mg, 90% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1); 1H NMR (600 MHz, CDCl3) δ 8.08 (d,
J = 7.7 Hz, 1H), 7.58−7.55 (m, 2H), 7.45−7.41 (m, 1H), 4.39 (q, J =
7.1 Hz, 2H), 4.22 (s, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 166.3, 133.0, 131.9, 131.5, 130.2, 128.7, 128.3,
118.0, 61.4, 23.2, 14.2. Spectroscopic data matches that reported in
the literature.4
Methyl 2-(cyanomethyl)benzoate (3ab). Following General
Procedure A: White solid, 14.0 mg, 80% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.07 (d, J
= 7.7 Hz, 1H), 7.58−7.57 (m, 2H), 7.46−7.39 (m, 1H), 4.22 (s, 2H),
3.93 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.8, 133.2,
132.1, 131.6, 130.2, 128.4, 128.3, 117.9, 52.3, 23.2. Spectroscopic data
matches that reported in the literature.13
130.2, 128.7, 128.3, 118.0, 67.0, 23.2, 22.0, 10.6. HRMS-ESI (m/z)
[M + Na]+ calculated for C12H13NNaO2 226.0838, found 226.0839.
Butyl 2-(cyanomethyl)benzoate (3ad). Following General Proce-
dure A: Colorless oil, 20.0 mg, 92% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.07 (d, J
= 7.6 Hz, 1H), 7.58−7.54 (m, 2H), 7.44−7.41 (m, 1H), 4.33 (t, J =
6.7 Hz, 2H), 4.22 (s, 2H), 1.81−1.70 (m, 2H), 1.53−1.41 (m, 2H),
0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.4,
133.0, 132.0, 131.5, 130.6, 128.7, 128.3, 118.0, 65.3, 30.7, 23.2, 19.3,
13.7. HRMS-ESI (m/z) [M + Na]+ calculated for C13H15NNaO2
240.0995, found 240.0997.
Isopropyl 2-(cyanomethyl)benzoate (3ae). Following General
Procedure A: Colorless oil, 15.0 mg, 74% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J
= 7.8 Hz, 1H), 7.57−7.54 (m, 2H), 7.42 (m, 1H), 5.26 (m, 1H), 4.21
(s, 2H), 1.39 (d, J = 6.3 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3)
δ 165.9, 132.9, 131.8, 131.5, 130.1, 129.2, 128.3, 118.0, 69.1, 23.2,
21.9. HRMS-ESI (m/z) [M + Na]+ calculated for C12H13NNaO2
226.0838, found 226.0840.
Cyclopentyl 2-(cyanomethyl)benzoate (3af). Following General
Procedure A: Colorless oil, 16.0 mg, 70% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J
= 7.8 Hz, 1H), 7.57−7.53 (m, 2H), 7.44−7.40 (m, 1H), 5.46−5.32
(m, 1H), 4.21 (s, 2H), 2.01−1.92 (m, 2H), 1.89−1.77 (m, 4H),
1.70−1.64 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.2,
132.9, 131.8, 131.5, 130.1, 129.1, 128.3, 118.0, 78.4, 32.8, 23.8, 23.2.
HRMS-ESI (m/z) [M + Na]+ calculated for C14H15NNaO2 252.0995,
found 252.0998.
Cyclohexyl 2-(cyanomethyl)benzoate (3ag). Following General
Procedure A: Colorless oil, 21.9 mg, 90% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.07 (d,
J = 7.7 Hz, 1H), 7.57−7.54 (m, 2H), 7.42 (m, 1H), 5.09−4.95 (m,
1H), 4.21 (s, 2H), 2.01−1.92 (m, 2H), 1.81−1.77 (m, 2H), 1.65−
1.52 (m, 3H), 1.50−1.40 (m, 2H), 1.39−1.30 (m, 1H); 13C{1H}
NMR (150 MHz, CDCl3) δ 165. 8, 132.9, 131.8, 131.5, 130.1, 129.2,
128.3, 118.0, 73.9, 31.2, 25.4, 23.8, 23.2. HRMS-ESI (m/z) [M +
Na]+ calculated for C15H17NNaO2 266.1152, found 266.1166.
4-Methylcyclohexyl 2-(cyanomethyl)benzoate (3ah). Following
General Procedure A: The diastereomeric ratio was 6:1 (Isomer 3ah′:
1
Isomer 3ah′′) as determined by H NMR analysis. Orange oil, 14.3
mg, 56% yield. (Rf = 0.2, petroleum ether/ethyl acetate = 20/1).
Isomer 3ah′: 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 7.8 Hz, 1H),
7.57−7.54 (m, 2H), 7.43−7.39 (m, 1H), 4.93−1.89 (m, 1H), 4.20 (s,
2H), 2.15−2.06 (m, 2H), 1.85−1.75 (m, 2H), 1.56−1.47 (m, 2H),
1.46−1.41 (m, 1H), 1.14−1.07 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 165.9, 132.9, 131.8, 131.5,
130.1, 129.2, 128.3, 118.0, 74.8, 33.0, 31.7, 29.8, 23.3, 21.8.
Isomer 3ah′′. 1H NMR (600 MHz, CDCl3) δ 8.08 (d, J = 7.7 Hz,
1H), 7.58−7.57 (m, 2H), 7.47−7.44 (m, 1H), 5.29−5.21 (m, 1H),
4.25 (s, 2H), 2.03−1.94 (m, 2H), 1.68−1.65 (m, 2H), 1.61−1.59 (m,
2H), 1.37−1.35 (m, 1H), 1.27 (m, 2H), 0.96 (d, J = 6.5 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 165.7, 132.9, 132.0, 131.5,
130.1, 129.3, 128.3, 118.0, 71.2, 31.7, 31.4, 29.6, 23.2, 22.1. HRMS-
ESI (m/z) [M + Na]+ calculated for C16H19NNaO2 280.1308, found
280.1307.
4-Ethylcyclohexyl 2-(cyanomethyl)benzoate (3ai). Following
General Procedure A: The diastereomeric ratio was 7:1 (Isomer
1
3ai′:Isomer 3ai′′) as determined by H NMR analysis. Colorless oil,
19.0 mg, 70% yield. (Rf = 0.2, petroleum ether/ethyl acetate = 20/1).
Isomer 3ai′: 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H),
7.55−7.54 (m, 2H), 7.44−7.40 (m, 1H), 4.95−4.89 (m, 1H), 4.20 (s,
2H), 2.18−2.08 (m, 2H), 1.91−1.83 (m, 2H), 1.54−1.45 (m, 2H),
1.29−1.22 (m, 2H), 1.21−1.15 (m, 1H), 1.11−1.02 (m, 2H), 0.90 (t,
J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.9, 132.9,
131.8, 131.5, 130.1, 129.2, 128.3, 118.0, 75.1, 38.4, 31.7, 30.6, 29.2,
23.3, 11.7.
Propyl 2-(cyanomethyl)benzoate (3ac). Following General
Procedure A: Colorless oil, 19.8 mg, 98% yield. (Rf = 0.20, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.08 (d, J
= 7.7 Hz, 1H), 7.58−7.56 (m, 2H), 7.45−7.40 (m, 1H), 4.29 (t, J =
6.7 Hz, 2H), 4.22 (s, 2H), 1.84−1.75 (m, 2H), 1.04 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.4, 133.0, 132.0, 131.5,
1
Isomer 3ai′′. H NMR (600 MHz, CDCl3) δ 8.08 (d, J = 7.5 Hz,
1H), 7.57−7.56 (m, 2H), 7.46−7.42 (m, 1H), 5.26−5.25 (m, 1H),
4.24 (s, 2H), 2.03−1.96 (m, 2H), 1.70−1.60 (m, 4H), 1.34−1.31 (m,
2H), 1.30−1.28 (m, 2H), 1.23−1.20 (m, 1H), 0.90 (t, J = 7.4 Hz,
10856
https://doi.org/10.1021/acs.joc.1c01131
J. Org. Chem. 2021, 86, 10852−10860

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.7, 132.9, 132.0, 131.5,
130.1, 129.3, 128.3, 118.0, 71.6, 38.1, 31.7, 29.7, 27.4, 23.2, 11.5.
HRMS-ESI (m/z) [M + Na]+ calculated for C17H21NNaO2 294.1465,
found 294.1461.
2-Hydroxyethyl 2-(cyanomethyl)benzoate (3aj). Following Gen-
eral Procedure A: Colorless oil, 20.3 mg, 98% yield. (Rf = 0.15,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
8.10 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 7.7 Hz,
1H), 7.43 (t, J = 7.6 Hz, 1H), 4.54−4.41 (m, 2H), 4.18 (s, 2H),
4.01−3.93 (m, 2H), 2.08 (s, 1H); 13C{1H} NMR (150 MHz, CDCl3)
δ 166.6, 133.3, 131.9, 131.7, 130.4, 128.5, 128.4, 118.2, 67.0, 61.0,
23.4. HRMS-ESI (m/z) [M + Na]+ calculated for C11H11NNaO3
228.0631, found 228.0630.
4-Hydroxybutyl 2-(cyanomethyl)benzoate (3ak). Following Gen-
eral Procedure A: Colorless oil, 23.1 mg, 99% yield. (Rf = 0.15,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
8.06 (d, J = 7.5 Hz, 1H), 7.65−7.52 (m, 2H), 7.46−7.36 (m, 1H),
4.37 (t, J = 6.6 Hz, 2H), 4.20 (s, 2H), 3.71 (t, J = 6.4 Hz, 2H), 1.91−
1.85 (m, 2H), 1.85 (s, 1H), 1.76−1.69 (m, 2H); 13C{1H} NMR (150
MHz, CDCl3) δ 166.4, 133.1, 132.0, 131.5, 130.3, 128.6, 128.4, 118.0,
65.3, 62.3, 29.2, 25.2, 23.2. HRMS-ESI (m/z) [M + H]+ calculated for
C13H16NO3 234.1125, found 234.1124.
1H), 7.43−7.38 (m, 1H), 6.50 (d, J = 3.2 Hz, 1H), 6.39 (dd, J = 3.2,
1.9 Hz, 1H), 5.31 (s, 2H), 4.22 (s, 2H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.9, 149.1, 143.5, 133.3, 132.2, 131.8, 130.1, 128.4, 128.1,
117.9, 111.1, 110.7, 58.8, 23.2. HRMS-ESI (m/z) [M + Na]+
calculated for C14H11NNaO3 264.0631, found 264.0639.
(Tetrahydrofuran-2-yl)methyl 2-(cyanomethyl)benzoate (3ar).
Following General Procedure B: Colorless oil, 16.9 mg, 69% yield.
1
(Rf = 0.20, petroleum ether/ethyl acetate = 20/1). H NMR (600
MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 1H), 7.58−7.55 (m, 2H), 7.43−
7.41 (m, 1H), 4.41−4.34 (m, 1H), 4.30−4.24 (m, 2H), 4.22 (s, 2H),
3.95−3.88 (m, 1H), 3.87−3.78 (m, 1H), 2.12−2.03 (m, 1H), 2.00−
1.87 (m, 2H), 1.71−1.63 (m, 1H); 13C{1H} NMR (150 MHz,
CDCl3) δ 166.3, 133.2, 132.1, 131.7, 130.1, 128.4, 128.4, 118.0, 76.4,
68.5, 67.3, 28.1, 25.7, 23.2. HRMS-ESI (m/z) [M + Na]+ calculated
for C14H15NNaO3 268.0944, found 268.0945.
Cinnamyl 2-(cyanomethyl)benzoate (3as). Following General
Procedure B: Colorless oil, 18.1 mg, 65% yield. (Rf = 0.2, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J
= 7.9 Hz, 1H), 7.59−7.57 (m, 2H), 7.47−7.40 (m, 3H), 7.34 (t, J =
7.6 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 6.76 (d, J = 15.9 Hz, 1H), 6.41
(dt, J = 15.8, 6.5 Hz, 1H), 4.99 (d, J = 6.5 Hz, 2H), 4.25 (s, 2H);
13C{1H} NMR (150 MHz, CDCl3) δ 166.1, 136.1, 135.0, 133.2,
2-Methoxyethyl 2-(cyanomethyl)benzoate (3al). Following Gen-
eral Procedure A: Colorless oil, 20.1 mg, 92% yield. (Rf = 0.5,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
8.10 (d, J = 8.2 Hz, 1H), 7.57 (m, 2H), 7.43 (m, 1H), 4.56−4.40 (m,
2H), 4.21 (s, 2H), 3.86−3.59 (m, 2H), 3.42 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 166.3, 133.2, 132.0, 131.8, 130.2, 128.4, 128.4,
118.0, 70.3, 64.3, 59.0, 23.2. HRMS-ESI (m/z) [M + H]+ calculated
for C12H14NO3 220.0968, found 220.0975.
2-Ethoxyethyl 2-(cyanomethyl)benzoate (3am). Following Gen-
eral Procedure A: Colorless oil, 22.6 mg, 97% yield. (Rf = 0.7,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
8.09 (d, J = 7.9 Hz, 1H), 7.60−7.51 (m, 2H), 7.48−7.38 (m, 1H),
4.52−4.41 (m, 2H), 4.21 (s, 2H), 3.83−3.73 (m, 2H), 3.58 (q, J = 7.0
Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3)
δ 166.3, 133.2, 132.0, 131.8, 130.2, 128.6, 128.3, 118.0, 68.2, 66.7,
64.5, 23.2, 15.2. HRMS-ESI (m/z) [M + H]+ calculated for
C13H16NO3 234.1125, found 234.1129.
But-3-en-1-yl 2-(cyanomethyl)benzoate (3an). Following Gen-
eral Procedure B: Colorless oil, 13.6 mg, 63% yield. (Rf = 0.20,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 8.06 (d, J = 7.7 Hz, 1H), 7.59−7.56 (m, 2H), 7.45−7.41 (m, 1H),
5.87 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.19 (dd, J = 17.1, 1.6 Hz, 1H),
5.13 (dd, J = 10.3, 1.5 Hz, 1H), 4.39 (t, J = 6.6 Hz, 2H), 4.21 (s, 2H),
2.59−2.48 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.3,
134.0, 133.1, 132.0, 131.6, 130.2, 128.6, 128.4, 117.9, 117.6, 64.4,
33.1, 23.3. HRMS-ESI (m/z) [M + Na]+ calculated for
C13H13NNaO2 238.0839, found 238.0843.
But-3-yn-1-yl 2-(cyanomethyl)benzoate (3ao). Following General
Procedure B: White solid, 19.1 mg, 89% yield. (Rf = 0.15, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.11 (d, J
= 7.6 Hz, 1H), 7.60−7.57 (m, 2H), 7.49−7.42 (m, 1H), 4.44 (t, J =
6.6 Hz, 2H), 4.23 (s, 2H), 2.69 (td, J = 6.6, 2.7 Hz, 2H), 2.05 (t, J =
2.7 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.0, 133.3,
132.1, 131.8, 130.2, 128.4, 128.2, 117. 9, 80.0, 70.3, 63.0, 23.3, 19.1.
HRMS-ESI (m/z) [M + Na]+ calculated for C13H11NNaO2 236.0682,
found 236.0687.
132.2, 131.7, 130.2, 128.7, 128.4, 128.3, 126.7, 122.7, 117.9, 66.0,
23.3. HRMS-ESI (m/z) [M + Na]+ calculated for C18H15NNaO2
300.0995, found 300.1004.
(1,3-Dihydroisobenzofuran-5-yl)methyl 2-(cyanomethyl)-ben-
zoate (3at). Following General Procedure C: Colorless oil, 25.6
mg, 87% yield. (Rf = 0.15, petroleum ether/ethyl acetate = 20/1). 1H
NMR (600 MHz, CDCl3) δ 8.08 (d, J = 7.7 Hz, 1H), 7.58−7.55 (m,
2H), 7.46−7.36 (m, 1H), 6.93−6.91 (m, 2H), 6.81 (d, J = 7.8 Hz,
1H), 5.97 (s, 2H), 5.25 (s, 2H), 4.21 (s, 2H); 13C{1H} NMR (150
MHz, CDCl3) δ 166.1, 147.9, 147.9, 133.2, 132.2, 131.7, 130.2, 129.2,
128.4, 128.3, 122.5, 117.9, 109.2, 108.4, 101.3, 67.1, 23.2. HRMS-ESI
(m/z) [M + Na]+ calculated for C17H13NNaO4 318.0737, found
318.0738.
3,7-Dimethyloct-6-en-1-yl 2-(cyanomethyl)benzoate (3au). Fol-
lowing General Procedure A: Colorless oil, 23.5 mg, 78% yield. (Rf =
1
0.3, petroleum ether/ethyl acetate = 20/1). H NMR (600 MHz,
CDCl3) δ 8.06 (d, J = 7.7 Hz, 1H), 7.60−7.54 (m, 2H), 7.46−7.37
(m, 1H), 5.11−5.08 (m, 1H), 4.42−4.28 (m, 2H), 4.23 (s, 2H),
2.07−1.95 (m, 2H), 1.85−1.81 (m, 1H), 1.67 (s, 3H), 1.63−1.60 (m,
1H), 1.60 (s, 3H), 1.58−1.52 (m, 1H), 1.44−1.36 (m, 1H), 1.27−
1.21 (m, 1H), 0.97 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 166.4, 133.0, 132.0, 131.5, 130.1, 128. 7, 128.3, 124.5,
118.0, 64.0, 37.0, 35.4, 29.6, 25.7, 25.4, 23.2, 19.5, 17.7. HRMS-ESI
(m/z) [M + Na]+ calculated for C19H25NNaO2 322.1777, found
322.1773.
3,7-Dimethyloctyl 2-(cyanomethyl)benzoate (3av). Following
General Procedure B: Colorless oil, 12.6 mg, 42% yield. (Rf = 0.20,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 8.06 (d, J = 7.6 Hz, 1H), 7.58−7.55 (m, 2H), 7.43 (m, 1H), 4.41−
4.28 (m, 2H), 4.23 (s, 2H), 1.87−1.75 (m, 1H), 1.54 (m, 2H), 1.38−
1.24 (m, 4H), 1.21−1.10 (m, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.87 (d, J
= 6.6 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.4, 133.0,
132.0, 131.5, 130.1, 128.7, 128.3, 118.0, 64.1, 39.2, 37.1, 35.5, 30.0,
28.0, 24.6, 23.2, 22.7, 22.6, 19.6. HRMS-ESI (m/z) [M + H]+
calculated for C19H28NO2 302.2114, found 302.2115.
(E)-3,7-Dimethylocta-2,6-dien-1-yl 2-(cyanomethyl)benzo-ate
(3aw). Following General Procedure B: Colorless oil, 17.8 mg, 60%
yield. (Rf = 0.3, petroleum ether/ethyl acetate = 20/1). 1H NMR (600
MHz, CDCl3) δ 8.07 (d, J = 7.5 Hz, 1H), 7.61−7.52 (m, 2H), 7.46−
7.34 (m, 1H), 5.47 (td, J = 7.1, 1.2 Hz, 1H), 5.09 (ddd, J = 6.9, 4.0,
1.3 Hz, 1H), 4.84 (d, J = 7.1 Hz, 2H), 4.23 (s, 2H), 2.15−2.11 (m,
2H), 2.10−2.06 (m, 2H), 1.77 (s, 3H), 1.67 (d, J = 0.6 Hz, 3H), 1.60
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.4, 143.1, 133.0,
131.9, 131.6, 130.1, 128.7, 128.3, 123.7, 118.0, 117.9, 62.2, 39.6, 26.3,
25.7, 23.2, 17.7, 16.6. HRMS-ESI (m/z) [M + Na]+ calculated for
C19H23NNaO2 320.1621, found 320.1620.
Benzyl 2-(cyanomethyl)benzoate (3ap). Following General
Procedure B: Colorless oil, 20.1 mg, 80% yield. (Rf = 0.15, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J
= 7.6 Hz, 1H), 7.58 (m, 2H), 7.48−7.34 (m, 6H), 5.37 (s, 2H), 4.23
(s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.1, 135.5, 133.3,
132.2, 131.7, 130.2, 128.7, 128.5, 128.4, 128.4, 128.3, 117.9, 67.2,
23.2. HRMS-ESI (m/z) [M + Na]+ calculated for C16H13NNaO2
274.0839, found 274.0841.
Furan-2-ylmethyl 2-(cyanomethyl)benzoate (3aq). Following
General Procedure B: Colorless oil, 17.7 mg, 73% yield. (Rf = 0.15,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 8.08 (d, J = 7.6 Hz, 1H), 7.58−7.55 (m, 2H), 7.46 (d, J = 1.4 Hz,
(Z)-3,7-Dimethylocta-2,6-dien-1-yl 2-(cyanomethyl)benzo-ate
(3ax). Following General Procedure B: Colorless oil, 19.9 mg, 67%
10857
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The Journal of Organic Chemistry
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Note
yield. (Rf = 0.3, petroleum ether/ethyl acetate = 20/1). 1H NMR (600
MHz, CDCl3) δ 8.10−7.96 (m, 1H), 7.62−7.51 (m, 2H), 7.46−7.34
(m, 1H), 5.48 (t, J = 7.2 Hz, 1H), 5.19−5.01 (m, 1H), 4.81 (d, J = 7.3
Hz, 2H), 4.23 (s, 2H), 2.21−2.16 (m, 2H), 2.13−2.11 (m, 2H), 1.80
(s, 3H), 1.67 (s, 3H), 1.60 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 166.3, 143.3, 133.0, 132.3, 132.0, 131.6, 130.0, 128.7, 128.3,
123.5, 118.8, 118.0, 62.0, 32.2, 26.7, 25.7, 23.5, 23.2, 17.7. HRMS-ESI
(m/z) [M + Na]+ calculated for C19H23NNaO2 320.1617, found
320.1620.
(4-(Prop-1-en-2-yl)cyclohex-1-en-1-yl)methyl 2-(cyanomethyl)-
benzoate (3ay). Following General Procedure B: Colorless oil, 17.0
mg, 58% yield. (Rf = 0.15, petroleum ether/ethyl acetate = 20/1). 1H
NMR (600 MHz, CDCl3) δ 8.09 (d, J = 7.7 Hz, 1H), 7.67−7.54 (m,
2H), 7.49−7.35 (m, 1H), 5.86 (s, 1H), 4.73 (dd, J = 12.3, 3.5 Hz,
4H), 4.24 (s, 2H), 2.24−2.14 (m, 4H), 2.06−1.94 (m, 1H), 1.92−
1.84 (m, 1H), 1.75 (s, 3H), 1.58−1.49 (m, 1H); 13C{1H} NMR (150
MHz, CDCl3) δ 166.2, 149.5, 133.1, 132.3, 132.1, 131.5, 130.1, 128.6,
128.3, 126.5, 118.0, 108.9, 69.4, 40.8, 30.5, 27.3, 26.6, 23.2, 20.8.
HRMS-ESI (m/z) [M + Na]+ calculated for C19H21NNaO2 318.1464,
found 318.1468.
( ( 1 R , 4 a R , 4 b R , 1 0 a R ) - 7 - I s o p r o p y l - 1 , 4 a - d i m e t h y l -
1,2,3,4,4a,4b,5,6,10,10a-decahydrophenanthren-1-yl)methyl 2-
(cyanomethyl)benzoate (3az). Following General Procedure C:
Colorless oil, 11.7 mg, 26% yield. (Rf = 0.3, petroleum ether/ethyl
acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz,
1H), 7.64−7.56 (m, 2H), 7.49−7.39 (m, 1H), 5.78 (s, 1H), 5.40 (d, J
= 2.4 Hz, 1H), 4.29−4.14 (m, 2H), 4.05 (d, J = 10.9 Hz, 1H), 3.95 (d,
J = 10.9 Hz, 1H), 2.24−2.20 (m, 1H), 2.15−2.01 (m, 4H), 1.90 (d, J
= 12.8 Hz, 2H), 1.85−1.78 (m, 1H), 1.70−1.62 (m, 1H), 1.58−1.53
(m, 2H), 1.49−1.46 (m, 1H), 1.28−1.21 (m, 2H), 1.11−1.07 (m,
1H), 1.05 (s, 3H), 1.01 (dd, J = 6.8, 5.0 Hz, 6H), 0.86 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 166.3, 145.4, 135.4, 133.1,
132.9, 130.3, 128.6, 127.0, 117.3, 61.7, 23.0, 14.2. HRMS-ESI (m/z)
[M + Na]+ calculated for C11H10ClNNaO2 246.0292, found 246.0300.
Ethyl 5-bromo-2-(cyanomethyl)benzoate (3fa). Following Gen-
eral Procedure D: White solid, 24.1 mg, 90% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 8.19 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.3, 2.2 Hz, 1H), 7.44 (d, J =
8.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 1.41 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.0, 135.9, 134.4,
131.7, 131.0, 130.3, 122.2, 117.4, 61.9, 22.8, 14.2. HRMS-ESI (m/z)
[M + Na]+ calculated for C11H10BrNNaO2 289.9787, found 289.9789.
Ethyl 4-bromo-2-(cyanomethyl)benzoate (3ga). Following Gen-
eral Procedure D: Yellow solid, 20.1 mg, 75% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 7.93 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.56 (dd, J = 8.4,
1.8 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 1.40 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.6, 133.9, 133.2,
132.9, 131.6, 127.8, 127.5, 117.3, 61.7, 22.9, 14.2. HRMS-ESI (m/z)
[M + Na]+ calculated for C11H10BrNNaO2 289.9787, found 289.9775.
Ethyl 3-bromo-2-(cyanomethyl)benzoate (3ha). Following Gen-
eral Procedure D: White solid, 21.7 mg, 81% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 7.98 (dd, J = 7.8, 1.2 Hz, 1H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.30
(t, J = 7.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.36 (s, 2H), 1.42 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.8, 137.1,
132.1, 131.4, 130.6, 129.7, 126.9, 116.7, 62.1, 22.5, 14.2. HRMS-ESI
(m/z) [M + Na]+ calculated for C11H10BrNNaO2 289.9787, found
289.9781.
Ethyl 2-(cyanomethyl)-3-(trifluoromethyl)benzoate (3ia). Fol-
lowing General Procedure D: White solid, 23.4 mg, 91% yield. (Rf
1
= 0.2, petroleum ether/ethyl acetate = 20/1). H NMR (600 MHz,
CDCl3) δ 8.22 (d, J = 7.3 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.57 (t, J
= 7.9 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.26 (s, 2H), 1.44 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.6, 134.9, 132.3,
130.7 (q, J = 30.2 Hz), 130.4, 130.1 (q, J = 5.7 Hz), 128.8, 123.6 (q, J
= 274.3 Hz), 116.9, 62.3, 18.6 (q, J = 2.6 Hz), 14.1. HRMS-ESI (m/z)
[M + Na]+ calculated for C12H10F3NNaO2 280.0556, found 280.0547.
Ethyl 3-cyano-2-(cyanomethyl)benzoate (3ja). Following Gen-
eral Procedure D: Colorless oil, 12.6 mg, 59% yield. (Rf = 0.4,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
8.30 (dd, J = 8.0, 1.4 Hz, 1H), 7.88 (dd, J = 7.8, 1.4 Hz, 1H), 7.59 (t, J
= 7.9 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.39 (s, 2H), 1.44 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.8, 136.7, 135.7,
135.3, 131.2, 129.4, 116.2, 115.9, 115.5, 62.5, 21.2, 14.1. HRMS-ESI
(m/z) [M + Na]+ calculated for C12H10N2NaO2 237.0634, found
237.0629.
Ethyl-2-(cyanomethyl)-4-(((3R,5S,8R,9S,10S,13R,14S,17R)-10,13-
dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahyd-ro-1H-
cyclopenta[a]phenanthren-3-yl)oxy)benzoate (3ka). Following
General Procedure D: White solid, 23.6 mg, 41% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 8.05 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.8,
2.2 Hz, 1H), 4.67 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.24 (s, 2H), 1.99
(d, J = 12.6 Hz, 1H), 1.91 (d, J = 14.4 Hz, 1H), 1.87−1.80 (m, 1H),
1.77−1.49 (m, 11H), 1.41 (d, J = 7.1 Hz, 3H), 1.36 (m, 3H), 1.31−
1.09 (m, 10H), 1.02 (dt, J = 18.3, 10.6 Hz, 4H), 0.92 (d, J = 6.5 Hz,
3H), 0.88 (dd, J = 6.6, 2.8 Hz, 6H), 0.85 (s, 3H), 0.68 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 166.1, 161.5, 134.4, 133.8,
119.9, 118.1, 117.6, 114.2, 72.7, 60.9, 56.5, 56.3, 54.1, 42.6, 40.0, 39.6,
39.5, 36.2, 35.84, 35.78, 35.5, 32.6, 32.5, 31.9, 28.4, 28.3, 28.0, 25.6,
24.2, 23.9, 23.5, 22.8, 22.6, 20.8, 18.7, 14.3, 12.1, 11.4. HRMS-ESI
(m/z) [M + Na]+ calculated for C38H57NNaO3 598.4231, found
598.4240.
Ethyl 2-(2-cyanopropan-2-yl)benzoate (3la). Following General
Procedure D: Colorless oil, 18.4 mg, 85% yield. (Rf = 0.2, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 7.62 (d, J
= 7.6 Hz, 1H), 7.47 (m, 2H), 7.40−7.31 (m, 1H), 4.43 (q, J = 7.2 Hz,
2H), 1.87 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 169.0, 139.4, 132.2, 131.3, 130.4, 127.8, 125.8, 124.3,
61.9, 36.6, 29.3, 14.1. HRMS-ESI (m/z) [M + Na]+ calculated for
C13H15NNaO2 240.0995, found 240.0994.
132.2, 131.3, 130.1, 128.6, 128.4, 122.4, 120.6, 117.9, 73.8, 50.8, 44.9,
38.8, 36.8, 36.6, 34.9, 34.8, 27.5, 24.1, 23.2, 22.7, 21.4, 20.8, 18.1,
17.9, 14.2. HRMS-ESI (m/z) [M + H]+ calculated for C29H38NO2
432.2824, found 432.2882.
Ethyl 2-(cyanomethyl)-5-methylbenzoate (3ba). Following Gen-
eral Procedure D: Colorless oil, 14.8 mg, 73% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
1
δ 7.87 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H), H NMR (600 MHz,
CDCl3) δ 7.42 (d, J = 7.8 Hz, 1H), 7.35 (dd, J = 7.8, 1.2 Hz, 1H),
4.37 (q, J = 7.1 Hz, 2H), 4.15 (s, 2H), 2.39 (s, 3H), 1.41 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.5, 138.3, 133.6,
132.0, 130.1, 128.9, 128.5, 118.2, 61.3, 22.7, 20.9, 14.3. HRMS-ESI
(m/z) [M + Na]+ calculated for C12H13NNaO2 226.0838, found
226.0833.
Ethyl 2-(cyanomethyl)-5-methoxybenzoate (3ca). Following
General Procedure D: White solid, 16.9 mg, 77% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
7.58 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 8.5,
2.8 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 3.85 (s, 3H), 1.41
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.1,
159.2, 131.4, 129.8, 123.7, 118.4, 118.3, 116.8, 61.5, 55.6, 22.5, 14.2.
HRMS-ESI (m/z) [M + Na]+ calculated for C12H13NNaO3 242.0787,
found 242.0784.
Ethyl 2-(cyanomethyl)-4,5-dimethoxybenzoate (3da). Following
General Procedure D: White solid, 15.7 mg, 63% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 8/2). 1H NMR (600 MHz, CDCl3) δ
7.57 (s, 1H), 6.98 (s, 1H), 4.37 (d, J = 7.1 Hz, 2H), 4.19 (s, 2H), 3.96
(s, 3H), 3.92 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 166.0, 152.5, 148.2, 126.0, 120.6, 118.3, 113.9, 112.6,
61.2, 56.2, 56.2, 23.0, 14.3. HRMS-ESI (m/z) [M + H]+ calculated for
C13H16NO4 250.1074, found 250.1075.
Ethyl 4-chloro-2-(cyanomethyl)benzoate (3ea). Following Gen-
eral Procedure D: White solid, 21.4 mg, 89% yield. (Rf = 0.2,
petroleum ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3)
δ 8.02 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.4,
2.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.21 (s, 2H), 1.40 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.5, 139.4, 133.9,
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Note
Ethyl 2-(3-cyanopropyl)benzoate (3ma). Following General
Procedure D: Colorless oil, 13.4 mg, 62% yield. (Rf = 0.2, petroleum
ether/ethyl acetate = 20/1). 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J
= 7.7 Hz, 1H), 7.45 (td, J = 7.5, 1.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H),
7.26 (d, J = 7.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.21−2.91 (m,
2H), 2.38 (t, J = 7.2 Hz, 2H), 2.01 (dd, J = 15.0, 7.4 Hz, 2H), 1.40 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.3, 141.9,
132.2, 131.2, 131.1, 129.7, 126.6, 119.7, 61.0, 33.4, 27.2, 16.9, 14.3.
HRMS-ESI (m/z) [M + Na]+ calculated for C13H15NNaO2 240.0995,
found 240.0992.
Scale-Up Reaction. Diethylamine (8.0 mmol, 2.0 equiv) was
added to a solution of oxime ester 1a (4.0 mmol, 1.0 equiv) in ethanol
(40 mL, 0.1 M) at room temperature. After 28 h, TLC indicated
complete conversion of the starting material and the solvent was
removed with a rotary evaporator. The pure product (3aa 0.67 g,
88%) was obtained by flash chromatography on silica gel using
petroleum ether and ethyl acetate as the eluent.
Rui Liu − Jiangsu Co-Innovation Center of Efficient Processing
and Utilization of Forest Resources, International Innovation
Center for Forest Chemicals and Materials, College of
Chemical Engineering, Nanjing Forestry University, Nanjing
210037, People’s Republic of China
Ping Jiang − Jiangsu Co-Innovation Center of Efficient
Processing and Utilization of Forest Resources, International
Innovation Center for Forest Chemicals and Materials,
College of Chemical Engineering, Nanjing Forestry
University, Nanjing 210037, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01131
Notes
The authors declare no competing financial interest.
Electrochemical Conditions. In an oven-dried undivided three-
necked flask (25 mL) equipped with a stir bar, 1a (0.3 mmol, 100 mg,
1.0 equiv), KI (50.0 mg, 1.0 equiv), ethanol (8.0 mL) were added.
The flask was equipped with graphite electrodes (1.0 cm × 1.0 cm ×
0.2 cm) as both the anode and cathode. The reaction mixture was
stirred and electrolyzed at a constant current of 10 mA under room
temperature for 8 h. TLC indicated complete conversion of the
starting material and the solvent was removed with a rotary
evaporator. The pure product (3aa 44.3 mg, 78%) was obtained by
flash chromatography on silica gel using petroleum ether and ethyl
acetate as the eluent.
In an oven-dried undivided three-necked flask (25 mL) equipped
with a stir bar, 1a (0.3 mmol, 100 mg, 1.0 equiv), KI (50.0 mg, 1.0
equiv), methanol (8.0 mL) were added. The flask was equipped with
graphite electrodes (1.0 cm × 1.0 cm × 0.2 cm) as both the anode
and cathode. The reaction mixture was stirred and electrolyzed at a
constant current of 10 mA under room temperature for 8 h. TLC
indicated complete conversion of the starting material and the solvent
was removed with a rotary evaporator. The pure product (3ab 26.8
mg, 51%) was obtained by flash chromatography on silica gel using
petroleum ether and ethyl acetate as the eluent.
ACKNOWLEDGMENTS
■
Financial support provided by the Natural Science Foundation
of China (21502094) is warmly acknowledged. C.D. thanks
the China Postdoctoral Science Foundation (2020M681619).
We are also grateful for support by the Advanced Analysis and
Testing Center of Nanjing Forestry University.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01131.
■
sı
1H NMR and 13C NMR spectra of all compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Shenlin Huang − Jiangsu Co-Innovation Center of Efficient
Processing and Utilization of Forest Resources, International
Innovation Center for Forest Chemicals and Materials,
College of Chemical Engineering, Nanjing Forestry University,
Nanjing 210037, People’s Republic of China; orcid.org/
0000-0001-7322-6981; Email: shuang@njfu.edu.cn
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Xiangtai Meng − Jiangsu Co-Innovation Center of Efficient
Processing and Utilization of Forest Resources, International
Innovation Center for Forest Chemicals and Materials,
College of Chemical Engineering, Nanjing Forestry
University, Nanjing 210037, People’s Republic of China
Dengfeng Chen − Jiangsu Co-Innovation Center of Efficient
Processing and Utilization of Forest Resources, International
Innovation Center for Forest Chemicals and Materials,
College of Chemical Engineering, Nanjing Forestry
University, Nanjing 210037, People’s Republic of China
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