Electrochemical Oxidative Coupling between Benzylic C(sp3)-H and N-H of Secondary Amines: Rapid Synthesis of α-Amino α-Aryl Esters

Article abstract of DOI:10.1021/acs.joc.1c00944

An intermolecular electrochemical coupling between the benzylic C(sp3)-H bond and various secondary amines is reported. The electronic behavior of two electronically rich units viz the α-position of α-aryl acetates and amines was engineered electrochemically, thus facilitating their reactivity for the direct access of α-amino esters. A series of acyclic/cyclic secondary amines and α-aryl acetates were tested to furnish the corresponding α-amino esters with high yields (up to 92%) under mild conditions.

Full text of DOI:10.1021/acs.joc.1c00944

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Article
Electrochemical Oxidative Coupling Between Benzylic C(sp3)−H and
N−H of Secondary Amines: Rapid Synthesis of α‑Amino α‑Aryl Esters
Yadav Kacharu Nagare, Imtiyaz Ahmad Shah, Jyothi Yadav, Amol Prakash Pawar, Rahul Choudhary,
Pankaj Chauhan, and Indresh Kumar*
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ABSTRACT: An intermolecular electrochemical coupling between the benzylic C(sp3)−H bond and various secondary amines is
reported. The electronic behavior of two electronically rich units viz the α-position of α-aryl acetates and amines was engineered
electrochemically, thus facilitating their reactivity for the direct access of α-amino esters. A series of acyclic/cyclic secondary amines
and α-aryl acetates were tested to furnish the corresponding α-amino esters with high yields (up to 92%) under mild conditions.
methods are mainly limited to the readily enolizable lower-
oxidation-state substrates, such as aldehydes/ketones (Scheme
1b), and hardly applicable to esters. The direct decarboxylative
coupling between highly activated acids and an amine is an
exciting way to access α-amino acid esters6 and other
methods.7 Thus, developing a direct, simple, and environ-
mentally friendly process accessing α-amino carbonyls such as
α-amino acid esters is highly desirable. Notably, α-amino acids
and their derivatives have medicinal significance and
importance in artificial sweeteners, food additives, and
cosmetic additives along with many other applications.8
On the other hand, electrochemical organic transformations
have recently gained much attention as sustainable protocols
under mild conditions.9 The electrochemical oxidative C−H
functionalizations for C−C,10 C−O,11 and C−N12 bond
formation have been achieved using metal-catalysis or metal-
free conditions. Despite these efforts, the direct electro-
chemical amination of the C(sp3)−H bond remains elusive.13
Herein, we present our efforts toward the synthesis of α-amino
acid esters through electrochemical oxidative coupling between
benzylic C(sp3)−H bonds and secondary amines. The protocol
offers a mild and direct access to various α-amino acid esters
INTRODUCTION
■
The α-amination of carbonyl compounds remains a trans-
formation of central importance in synthetic and medicinal
chemistry as a straightforward route to versatile building units
widely present in natural products and pharmaceuticals.1 A
reaction between nucleophilic synthons of carbonyl com-
pounds, such as enolates or enamines, and preformed
electrophilic amine reagents is a well-explored technique to
access α-amino carbonyls.2 Besides, the reaction between
prefunctionalized carbonyls and nucleophilic amines (N−δ) has
also been explored along with other conventional methods.3
The direct C(sp3)−H functionalization would offer a
straightforward approach to introduce functionality to organic
skeletons.4 The direct dehydrogenative C−N bond formation
between the proximal position of carbonyls and the
nucleophilic amine is the shortest route to access α-amino
carbonyls. However, it requires a polarity reversal of two
electronically mismatched units.5 In this context, MacMillan
and co-workers developed a direct α-amination of ketones,
esters, and aldehydes with secondary amines under the Cu-
catalyzed aerobic condition (Scheme 1a).5a Initially, the direct
NIS-mediated oxidative coupling between the secondary amine
and ketones was explored by Prabhu and co-workers using
peroxide as a co-oxidant.5b A similar NBS-mediated protocol
for oxidative α-amination of in situ-generated ketones was
developed by Sekar and co-workers.5c Guo and co-workers
developed an NH4I/peroxide-mediated α-amination of keto-
nes.5d Liang et al. recently developed an electrochemical
oxidative coupling between ketones and secondary amines to
access α-amino ketones.5e Despite remarkable recent advances
made in accessing α-amino carbonyls, more strictly, these
Received: April 23, 2021
Published: June 29, 2021
https://doi.org/10.1021/acs.joc.1c00944
© 2021 American Chemical Society
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Scheme 1. Background for the Direct α-Amination of Carbonyls and the Present Work on Electrochemical Amination of α-
Aryl Acetates
under metal-free conditions while tolerating organic function-
alities (Scheme 1c).
obtained in 89% yield under optimized conditions (entry 1,
Table 1). Next, either increasing (entry 2, Table 1) or
decreasing the applied current (entry 3, Table 1) from
standard conditions to the vessel reduces the reaction yields. A
similar result with 65% yield was obtained using C(+)/C(−)
electrodes under standardized conditions (entry 4, Table 1).
No desired product 3 was detected by switching the electrode
position in the absence of KI and electric current (entries 5−7,
Table 1). The addition of bases (1.0 equiv) under standard
conditions (entries 8−9, Table 1) or varying solvent medium
(entry 10, Table 1) did not improve the reaction yields. Thus,
we prefer to perform the reaction under optimized conditions.
With the optimal conditions in hand, the reaction scope was
investigated with various esters and amines (Table 2). Initially,
pyrrolidine was tested with multiple meta-chlorophenyl acetic
esters (-Me, -Et, -iPr, -tert-butyl), which furnished the
corresponding α-amino esters 3−6 (up to 89%). Moreover,
different ortho-chlorophenyl acetic esters (i.e., -Me, -Et, -allyl,
-cyclohexyl, -benzyl, and -piperonyl) were initially employed
with pyrrolidine to finish the corresponding α-amino esters 7−
12 (up to 76%). Next, a series of methyl and ethyl α-aryl
acetates having substitutions (halogens/electron-withdrawing
group) at different aromatic ring positions were tested with
pyrrolidine, which furnished the corresponding products 13−
20 (up to 85%). However, the reaction did not produce the
desired outcome in the presence of electron-donating groups
(see the SI). The scope of various acyclic/cyclic secondary
amines was tested with methyl 2-(3-chlorophenyl) acetate 1 to
yield the corresponding products 21−28 (up to 92%). A
similar trend was observed in the formation of 29−32 and 33−
36, where piperidine and morpholine, respectively, were
coupled with various esters. The protocol was extended with
a secondary amine that exists in cetirizine, a drug molecule,
and complementary product 37 was obtained with 68% yield
under optimized conditions. Presently, the developed method
RESULTS AND DISCUSSION
■
At the outset of our investigation, methyl 2-(3-chlorophenyl)
acetate 1 and pyrrolidine 2 were employed as model substrates
(Table 1). Extensive experiments for finding suitable reaction
parameters such as electrodes, electrolyte, catalyst, and solvents
(Tables S1−S4; see the Supporting Information, SI) were
performed, which led to identifying the optimal reaction
conditions. To our delight, the desired α-amino ester 3 was
ab
Table 1. Standardization of Reaction Conditions
entry
variation from standard conditions
none
I = 10.0 mA, instead of I = 8.0 mA
I = 6.0 mA, instead of I = 8.0 mA
C(+)/C(−) used instead of C(+)/Cu(−)
Cu(+)/C(−) used instead of C(+)/Cu(−)
without KI
yield (%)
1
2
3
4
5
89
56
71
58
6
7
without electricity
8
9
10
lutidine (1.0 equiv) used as additive
K2CO3 (1.0 equiv) used as additive
MeOH as solvent instead of CH3CN
74
68
45
a
Reaction conditions: 1 (1.0 mmol), 2 (3.0 mmol), KI (0.5 mmol),
LiClO4 (1.0 mmol) in MeCN (10 mL), C-anode, Cu-cathode,
undivided cell, constant current = 8 mA, at room temperature (rt)
b
under a N2 atmosphere for 14 h. All isolated yields were based on 1.
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a
Table 2. Generality Concerning Various Esters and Amines
a
Reaction conditions: ester (1.0 mmol), amine (3.0 mmol), KI (0.5 mmol), LiClO4 (1.0 mmol) in MeCN (10 mL), C-anode, Cu-cathode,
b
undivided cell, constant current = 8 mA, at rt under a N2 atmosphere for 12−20 h. All isolated yields were based on ester.
is mainly limited to α-aryl acetates and secondary aliphatic
amines. The reaction failed to give α-amino-α-aryl acetates
with aniline(s)/primary/secondary aromatic amines or with
sterically hindered aromatic esters/acids/amide as well as
aliphatic ester under optimized conditions (see the SI for
details).
For clarification of the reaction mechanism, electroanalytical
measurements were performed. The cyclic voltammogram
(CV) of KI with LiClO4, as an electrolyte, showed a redox
potential (peak potentials: +0.211 and −0.911 V vs Ag/AgCl
as the reference electrode). The CVs of substrates 1, KI, and
LiClO4 showed an oxidation potential of +1.30 V vs Ag/AgCl
as the reference electrode. Finally, the CVs of all of the reacting
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species 1, 2, KI, and LiClO4 showed an oxidation potential of
+1.05 V vs Ag/AgCl as a reference electrode (Figure 1). The
formation of the iodo-compound 38 through the combination
of ester 1 with in situ-generated I2 could be the initial outcome
before reacting with amine 2.
Scheme 2. (a) Set of Controlled Experiments, (b) Proposed
Reaction Mechanism for the Electrochemical Amination of
α-Aryl Acetates
Figure 1. Cyclic voltammograms of CH3CN/LiClO4 (10 mL, 0.1M)
(black); KI (0.01M) in CH3CN/LiClO4 (10 mL, 0.1M) (red); ester 1
(0.01M) and KI (0.01M) in CH3CN/LiClO4 (10 mL, 0.1M) (blue);
ester 1 (0.01M), pyrrolidine 2 (0.01M), and KI (0.01M) in CH3CN/
LiClO4 (10 mL, 0.1M); reference electrode: Ag/AgCl (3M KCl);
scan rate: 0.2 V/s.
A set of control experiments was performed to gain more
mechanistic insights into the electrochemical process. Initially,
α-iodo-α-aryl methyl acetate 38 (45%) was isolated when a
controlled experiment was conducted with amine 2 (1.0 equiv)
under optimized conditions (Scheme 2a-i). The resulting iodo-
ester 38 was separately reacted with amine 2 (2.5 equiv) to
furnish 3 (89% yield), which confirms that the reaction
proceeds through α-iodination, followed by displacement with
the amine to provide the desired compound (Scheme 2a-ii).
On the other hand, formation of product 3 was not observed
with BHT or TEMPO, as a radical scavenger, under the
standard electrochemical conditions, confirming the radical
nature of the reaction at the intermediate steps (Scheme 2a-
iii).
We proposed a reaction mechanism based on the cyclic
voltammogram (CV) and other controlled experimental
observations (Scheme 2b). Ester 38 could be generated
through a radical pathway in which intermediate (A)
developed through the sequential reaction with radical iodine
(I*). Once the critical intermediate 38 is formed, it soon
undergoes a nucleophilic substitution reaction with an amine,
leading to the final α-amination product 3, accompanying the
second molecular HI. Simultaneously, the in situ-generated HI
is reduced to evolve H2 on the cathode surface and regenerate
the iodide ion and the step of α-iodination of ester 1, thus
requiring a catalytic amount of KI. Alternatively, ester 1 could
react with molecular iodine, in situ-generated through the
anodic oxidation, to α-iodo-ester 38, which will undergo a
displacement reaction with an amine.
Besides, synthetic conversion of ester 22 was performed to the
corresponding azido compound 39 (58% yield) with a three-
step protocol (eq 2, Scheme 3). Similarly, α-amino ester 30
was efficiently transformed to the corresponding amide 40
(76% yield) (eq 3, Scheme 3).
CONCLUSIONS
■
In summary, we have developed an efficient electrochemical
protocol for intermolecular oxidative coupling between α-aryl
acetates (C(sp3)−H bond) and secondary amines (N−H
bond). The mild electrocatalytic condition furnishes α-amino
esters by stitching together two electronically mismatched
units through C−N-bond formation, with a high yield (up to
92%). The reactions can be scaled up without impacting the
process efficiency, and the resulting α-amino esters can be
functionalized to other similar biorelevant compounds. Further
study in this direction is underway.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all commercially
available compounds were used as received without further
purification. Graphite and other electrodes were purchased from
IKA, and all of the electrochemical reactions were performed under
N2 at room temperature using IKA Electrasyn 2.0. Cyclic
voltammetric (CV) experiments were performed using the CH
Instruments electrochemical analyzer (model CHI1200B). CH3CN
and other solvents were obtained from Merck Life Science Private
Limited and were distilled from appropriate drying agents before
being used in the reactions. All of the α-aryl acetates were prepared
using the reported procedure.14 Reactions under the standard
The practical utility of the developed electrochemical
protocol was demonstrated for the gram scale, and 22 (1.30
g, 90% yield) was obtained without much variation in the
product yield under optimized conditions (eq 1, Scheme 3).
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Scheme 3. Gram-Scale Synthesis and Synthetic Applications to Azido- and Amide Compounds
conditions were monitored by thin-layer chromatography (TLC) on
Merck silica gel 60 F254 precoated plates (0.25 mm) under UV light
at 254 nm. Column chromatographic purification was performed on
silica gel (100−200 mesh) using an eluent of petroleum ether and
ethyl acetate. Chemical yields refer to pure (>95% purity by 1H
NMR), isolated substances. NMR spectroscopy was recorded on a
128.5, 128.4, 126.5,73.4, 61.7, 52.4 (2C), 23.3 (2C), 14.0. HRMS
(ESI-TOF) m/z: [M + H+] calcd for C14H19ClNO2 268.1099, found
268.1098.
Isopropyl 2-(3-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 5).
Purification with petroleum ether/EtOAc (9:1) as the eluent;
1
colorless liquid (228 mg, 81% yield). H NMR (400 MHz, CDCl3)
1
400 MHz NMR spectrometer (Bruker). H and 13C NMR spectra
δ 7.51 (d, J = 2.1 Hz, 1H), 7.40−7.36 (m, 1H), 7.32−7.25 (m, 2H),
5.04 (hept, J = 6.6 Hz, 1H), 3.85 (s, 1H), 2.63−2.52 (m, 2H), 2.46
(td, J = 8.2, 7.1, 5.1 Hz, 2H), 1.81 (ddd, J = 6.3, 4.9, 2.5 Hz, 4H), 1.24
(d, J = 6.2 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 170.7, 139.7, 134.3, 129.6, 128.5, 128.3, 126.5, 73.6,
68.5, 52.4 (2C), 23.4 (2C), 21.7, 21.4. HRMS (ESI-TOF) m/z: [M +
H+] calcd for C15H21ClNO2 282.1255, found 282.1263.
were recorded in CDCl3 and calibrated to the solvent resonance as an
internal standard (1H NMR, CDCl3 at 7.26 ppm, 13C NMR, CDCl3 at
77.0 ppm). High-resolution mass spectra were recorded on Agilent
6545 Q-TOF LC/MS. Melting points were determined by the EZ-
Melt automated melting point apparatus and are incorrect.
General Procedure for Electrochemical α-Amination of
Esters. A 10 mL dried undivided reaction cell equipped with a
stirring bar was charged with appropriate α-aryl acetates 1 (1.0 mmol,
1.0 equiv), secondary amine 2 (3.0 mmol, 3.0 equiv), KI (83 mg, 0.5
mmol, 0.5 equiv), and LiClO4 (106 mg, 1.0 mmol, 1.0 equiv)
dissolved in CH3CN (10.0 mL). The reaction mixture was
electrolyzed using a graphite plate as the anode and a copper plate
as the cathode at a constant current condition (8 mA) under a N2
atmosphere at room temperature. TLC monitored the reaction
progress. The reaction mixture was evaporated under reduced
pressure, and the residue mass was quenched by stirring between a
saturated aqueous Na2S2O3 solution (5.0 mL) and ethyl acetate (10.0
mL). The organic layer was separated and dried with anhydrous
Na2SO4 and evaporated under reduced pressure. Purification on silica
gel column chromatography using a mixture of petroleum ether and
ethyl acetate (9:1 to 1:1) as the eluent afforded pure α-amino α-aryl
esters 3 (up to 92% yield).
Methyl 2-(3-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 3). Puri-
fication with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (226 mg, 89% yield).1H NMR (400 MHz, CDCl3) δ 7.49 (d, J
= 2.0 Hz, 1H), 7.37−7.33 (m, 1H), 7.29−7.23 (m, 2H), 3.90 (s, 1H),
3.68 (s, 3H), 2.54 (td, J = 7.0, 2.6 Hz, 2H), 2.44 (qt, J = 4.5, 1.8 Hz,
2H), 1.80 (ddd, J = 6.4, 4.7, 2.3 Hz, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 171.5, 139.2, 134.4, 129.7, 128.4 (2C), 126.5, 73.2, 52.4
(2C), 52.1, 23.2. HRMS (ESI-TOF) m/z: [M + H+] calcd for
C13H17ClNO2 254.0942, found 254.0941.
tert-Butyl 2-(3-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 6).
Purification with petroleum ether/EtOAc (9:1) as the eluent;
1
colorless liquid (213 mg, 72% yield). H NMR (400 MHz, CDCl3)
δ 7.51 (d, J = 2.0 Hz, 1H), 7.41−7.37 (m, 1H), 7.29 (dd, J = 4.8, 1.7
Hz, 2H), 3.82 (s, 1H), 2.64−2.56 (m, 2H), 2.54−2.45 (m, 2H),
1.84−1.80 (m, 4H), 1.42 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3)
δ 170.2, 139.8, 134.2, 129.5, 128.4, 128.1, 126.5, 81.4, 73.8, 52.2
(2C), 27.8 (3C), 23.3 (2C). HRMS (ESI-TOF) m/z: [M + H+] calcd
for C16H23ClNO2 296.1412, found 295.1319.
Methyl 2-(2-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 7). Puri-
fication with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (193 mg, 76% yield), 1H NMR (400 MHz, CDCl3) δ 7.68 (dd,
J = 7.7, 1.9 Hz, 1H), 7.36 (dd, J = 7.8, 1.5 Hz, 1H), 7.29−7.24 (m,
1H), 7.21 (td, J = 7.6, 1.9 Hz, 1H), 4.67 (s, 1H), 3.68 (s, 3H), 2.63
(qd, J = 6.7, 3.0 Hz, 2H), 2.49 (td, J = 7.2, 2.5 Hz, 2H), 1.79 (dt, J =
6.1, 3.0 Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 134.9,
133.9, 130.0, 129.6, 129.1, 127.1, 67.8, 52.1 (2C), 52.0 (2C), 23.3.
HRMS (ESI-TOF) m/z: [M + H+] calcd for C13H17ClNO2 254.0942,
found 254.0938.
Ethyl 2-(2-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 8). Purifi-
cation with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (198 mg, 74% yield), 1H NMR (400 MHz, CDCl3) δ 7.72 (dd,
J = 7.7, 1.9 Hz, 1H), 7.39 (dd, J = 7.8, 1.5 Hz, 1H), 7.29 (td, J = 7.4,
1.6 Hz, 1H), 7.23 (td, J = 7.6, 1.9 Hz, 1H), 4.66 (s, 1H), 4.25−4.10
(m, 2H), 2.66 (td, J = 7.1, 2.4 Hz, 2H), 2.52 (td, J = 7.2, 2.5 Hz, 2H),
1.81 (dd, J = 6.3, 3.2 Hz, 4H), 1.22 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 171.2, 135.0, 133.9, 130.0, 129.5, 129.0,
127.0, 68.0, 61.0, 52.0 (2C), 23.3 (2C), 14.1. HRMS (ESI-TOF) m/z:
[M + H+] calcd for C14H19ClNO2 268.1099, found 268.1095.
Allyl 2-(2-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 9). Purifica-
tion with petroleum ether/EtOAc (9:1) as the eluent; colorless liquid
Ethyl 2-(3-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 4). Purifi-
cation with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (228 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J
= 2.1 Hz, 1H), 7.38 (dt, J = 6.3, 2.0 Hz, 1H), 7.30−7.26 (m, 2H),
4.27−4.08 (m, 2H), 3.89 (s, 1H), 2.57 (dd, J = 6.8, 2.2 Hz, 2H),
2.52−2.41 (m, 2H), 1.86−1.78 (m, 4H), 1.22 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 139.5, 134.4, 129.7,
1
(204 mg, 73% yield), H NMR (400 MHz, CDCl3) δ 7.74 (dd, J =
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7.6, 1.7 Hz, 1H), 7.40 (dd, J = 7.8, 1.4 Hz, 1H), 7.32−7.22 (m, 2H),
5.86 (ddt, J = 16.1, 10.8, 5.5 Hz, 1H), 5.28−5.16 (m, 2H), 4.74 (s,
1H), 4.68−4.56 (m, 2H), 2.70 (dt, J = 10.5, 5.3 Hz, 2H), 2.59−2.50
(m, 2H), 1.90−1.76 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ
170.7, 134.8, 133.9, 131.7, 130.1, 129.5, 129.1, 127.1, 118.1, 67.9,
65.4, 52.1 (2C), 23.3 (2C). HRMS (ESI-TOF) m/z: [M + H+] calcd
for C15H19ClNO2 280.1099, found 280.1106.
2.56 (dt, J = 6.0, 3.2 Hz, 2H), 2.48−2.41 (m, 2H), 1.82 (td, J = 5.7,
3.1 Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 136.4, 131.7
(2C), 130.1 (2C), 122.3, 73.2, 52.5 (2C), 52.2, 23.3 (2C). HRMS
(ESI-TOF) m/z: [M + H+] calcd for C13H17BrNO2 298.0437, found
298.0424.
Methyl 2-(Pyrrolidin-1-yl)-2-(4-(tosyloxy)phenyl)acetate ( 17).
Purification with petroleum ether/EtOAc (8:2) as the eluent;
1
Benzo[d][1,3]dioxol-5-ylmethyl-2-(2-chlorophenyl)-2-(pyrrolidin-
colorless liquid (304 mg, 78% yield). H NMR (400 MHz, CDCl3)
1-yl)acetate ( 10). Purification with petroleum ether/EtOAc (8:2)
δ 7.73 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.0
Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 3.92 (s, 1H), 3.70 (s, 3H), 2.57−
2.50 (m, 2H), 2.47 (s, 3H), 2.44−2.37 (m, 2H), 1.81 (td, J = 10.2,
8.5, 5.3 Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.7, 149.5,
145.4, 136.2, 132.5, 129.8 (2C), 129.7 (2C), 128.5 (2C), 122.5 (2C),
73.0, 52.5 (2C), 52.3, 23.3 (2C), 21.7. HRMS (ESI-TOF) m/z: [M +
H+] calcd for C20H24NO5S 390.1370, found 390.1377.
Ethyl 2-Phenyl-2-(pyrrolidin-1-yl)acetate ( 18). Purification with
petroleum ether/EtOAc (9:1) as the eluent; colorless liquid (180 mg,
77% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (dt, J = 8.4, 2.2 Hz,
2H), 7.34−7.27 (m, 3H), 4.22−4.06 (m, 2H), 3.89 (s, 1H), 2.55 (td,
J = 7.1, 2.4 Hz, 2H), 2.47−2.38 (m, 2H), 1.83−1.73 (m, 4H), 1.18 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 137.4,
128.4 (2C), 128.3 (2C), 128.1, 73.9, 60.8, 52.4 (2C), 23.3 (2C), 14.0.
HRMS (ESI-TOF) m/z: [M + H+] calcd for C14H20NO2 234.1489,
found 234.1486.
Ethyl 2-(4-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 19). Purifi-
cation with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (212 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J
= 8.4 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 4.21−4.09 (m, 2H), 3.89 (s,
1H), 2.56 (ddd, J = 8.7, 7.4, 4.2 Hz, 2H), 2.44 (ddd, J = 9.7, 7.7, 4.3
Hz, 2H), 1.81 (td, J = 5.8, 3.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.4, 136.1, 134.0, 129.7 (2C),
128.7 (2C), 73.3, 61.1, 52.4 (2C), 23.3 (2C), 14.1. HRMS (ESI-
TOF) m/z: [M + H+] calcd for C14H19ClNO2 268.1099, found
268.1096.
Ethyl 2-(4-Bromophenyl)-2-(pyrrolidin-1-yl)acetate ( 20). Purifi-
cation with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (240 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J
= 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.20−4.05 (m, 2H), 3.84 (s,
1H), 2.52 (td, J = 7.1, 2.4 Hz, 2H), 2.45−2.37 (m, 2H), 1.82−1.73
(m, 4H), 1.17 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 171.2, 136.5, 131.6 (2C), 130.0 (2C), 122.1, 73.2, 61.0, 52.4 (2C),
23.3 (2C), 14.0. HRMS (ESI-TOF) m/z: [M + H+] calcd for
C14H19BrNO2 312.0594, found 312.0571.
1
as the eluent; colorless liquid (254 mg, 68% yield). H NMR (400
MHz, CDCl3) δ 7.68 (dd, J = 7.5, 2.0 Hz, 1H), 7.36 (dd, J = 7.5, 1.8
Hz, 1H), 7.28−7.18 (m, 2H), 6.72 (s, 3H), 5.92 (s, 2H), 5.09−4.98
(m, 2H), 4.71 (s, 1H), 2.63 (td, J = 7.1, 2.3 Hz, 2H), 2.53−2.45 (m,
2H), 1.79 (dt, J = 6.0, 3.0 Hz, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 170.9, 147.5, 147.3, 134.7, 133.8, 130.0, 129.4, 129.3, 129.0,
126.9, 121.8, 108.6, 107.9, 100.9, 67.8, 66.4, 51.9 (2C), 23.3 (2C).
HRMS (ESI-TOF) m/z: [M + H+] calcd for C20H21ClNO4 374.1154,
found 374.1158.
Benzyl 2-(2-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 11). Pu-
rification with petroleum ether/EtOAc (8:2) as the eluent; colorless
liquid (231 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.66 (dd,
J = 7.4, 2.1 Hz, 1H), 7.35 (dd, J = 7.2, 2.1 Hz, 1H), 7.28−7.22 (m,
4H), 7.19 (td, J = 5.4, 2.5 Hz, 3H), 5.12 (q, J = 12.5 Hz, 2H), 4.71 (s,
1H), 2.61 (td, J = 7.1, 2.2 Hz, 2H), 2.52−2.44 (m, 2H), 1.77 (dt, J =
6.1, 3.1 Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.0, 135.7,
134.8, 133.9, 130.1, 129.5, 129.0, 128.4 (2C), 128.0, 127.8 (2C),
127.1, 67.9, 66.5, 52.0 (2C), 23.4 (2C). HRMS (ESI-TOF) m/z: [M
+ H+] calcd for C19H21ClNO2 330.1255, found 330.1173.
Cyclohexyl 2-(2-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 12).
Purification with petroleum ether/EtOAc (9:1) as the eluent;
1
colorless liquid (222 mg, 69% yield), H NMR (400 MHz, CDCl3)
δ 7.75−7.70 (m, 1H), 7.35 (dd, J = 7.8, 1.4 Hz, 1H), 7.29−7.17 (m,
2H), 4.80 (tt, J = 8.4, 3.7 Hz, 1H), 4.63 (s, 1H), 2.72−2.62 (m, 2H),
2.56−2.47 (m, 2H), 1.84−1.75 (m, 5H), 1.72−1.60 (m, 2H), 1.47
(m, 3H), 1.30 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.4,
135.2, 133.8, 130.0, 129.4, 128.9, 127.0, 73.0, 68.2, 52.1 (2C), 31.3,
31.0, 25.3, 23.4 (3C), 23.2. HRMS (ESI-TOF) m/z: [M + H+] calcd
for C18H25ClNO2 322.1568, found 322.1561.
Methyl 2-Phenyl-2-(pyrrolidin-1-yl)acetate ( 13). Purification
with petroleum ether/EtOAc (9:1) as the eluent; colorless liquid
1
(178 mg, 81% yield). H NMR (400 MHz, CDCl3) δ 7.39 (dd, J =
7.8, 1.6 Hz, 2H), 7.27−7.20 (m, 3H), 3.86 (s, 1H), 3.59 (s, 3H),
2.52−2.45 (m, 2H), 2.36 (dd, J = 10.5, 3.2 Hz, 2H), 1.72 (td, J = 9.8,
8.3, 5.1 Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 137.1,
128.4 (2C), 128.3 (2C), 128.2, 73.7, 52.4 (2C), 52.0, 23.2 (2C).
HRMS (ESI-TOF) m/z: [M + H+] calcd for C13H18NO2 220.1332,
found 220.1328.
Methyl 2-(2-Fluorophenyl)-2-(pyrrolidin-1-yl)acetate ( 14). Pu-
rification with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (168 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 7.60 (td, J
= 7.5, 1.7 Hz, 1H), 7.33−7.26 (m, 1H), 7.19−7.13 (m, 1H), 7.10−
7.03 (m, 1H), 4.50 (s, 1H), 3.71 (s, 3H), 2.63 (dt, J = 10.7, 5.3 Hz,
2H), 2.51 (dt, J = 7.9, 5.1 Hz, 2H), 1.85−1.77 (m, 4H). 13C{1H}
NMR (101 MHz, CDCl3) δ 171.6, 160.5 (d, J = 247.3 Hz), 130.0 (d,
J = 3.4 Hz), 129.6 (d, J = 8.3 Hz), 124.3 (d, J = 3.5 Hz), 123.9 (d, J =
13.4 Hz), 115.5 (d, J = 22.5 Hz), 64.0, 52.1, 51.9 (2C), 23.3 (2C).
HRMS (ESI-TOF) m/z: [M + H+] calcd for C13H17FNO2 238.1238,
found 238.1235.
Methyl 2-(4-Chlorophenyl)-2-(pyrrolidin-1-yl)acetate ( 15). Pu-
rification with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (216 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J
= 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 3.90 (s, 1H), 3.68 (s, 3H),
2.58−2.50 (m, 2H), 2.46−2.38 (m, 2H), 1.80 (td, J = 5.7, 3.1 Hz,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.2, 135.8, 134.10 129.6
(2C), 128.7 (2C), 73.0, 52.4 (C), 52.1, 23.2 (2C). HRMS (ESI-TOF)
m/z: [M + H+] calcd for C13H17ClNO2 254.0942, found 254.0937.
Methyl 2-(4-Bromophenyl)-2-(pyrrolidin-1-yl)acetate ( 16). Pu-
rification with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (246 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J
= 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 3.91 (s, 1H), 3.70 (s, 3H),
Methyl 2-(3-Chlorophenyl)-2-(diethyl amino)acetate ( 21).
Purification with petroleum ether/EtOAc (9:1) as the eluent;
1
colorless liquid (208 mg, 81% yield). H NMR (400 MHz, CDCl3)
δ 7.49−7.45 (m, 1H), 7.35−7.26 (m, 3H), 4.48 (s, 1H), 3.74 (s, 3H),
2.62 (q, J = 7.1 Hz, 4H), 1.02 (t, J = 7.2 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 172.2, 139.3, 134.3, 129.6, 128.7, 128.1, 126.8,
68.7, 51.8, 43.7 (2C), 12.0 (2C). HRMS (ESI-TOF) m/z: [M + H+]
calcd for C13H19ClNO2 256.1099, found 256.1096.
Methyl 2-(3-Chlorophenyl)-2-(piperidin-1-yl)acetate ( 22). Puri-
fication with petroleum ether/EtOAc (9:1) as the eluent; light-yellow
liquid (246 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J
= 2.0 Hz, 1H), 7.34−7.30 (m, 1H), 7.30−7.23 (m, 2H), 3.96 (s, 1H),
3.69 (s, 3H), 2.37 (m, 4H), 1.59 (quin, J = 5.5 Hz, 4H), 1.43 (m, J =
6.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 138.3,
134.3, 129.6, 128.7, 128.3, 126.8, 74.2, 52.2 (2C), 51.9, 25.7 (2C),
24.2. HRMS (ESI-TOF) m/z: [M + H+] calcd for C14H19ClNO2
268.1099, found 268.1104.
Methyl 2-(3-Chlorophenyl)-2-(4-hydroxypiperidin-1-yl)acetate
( 23). Purification with petroleum ether/EtOAc (7:3) as the eluent;
colorless liquid (222 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ
7.43 (s, 1H), 7.32−7.23 (m, 3H), 4.01 (s, 1H), 3.69 (s, 3H), 2.70
(ddt, J = 14.9, 9.1, 4.5 Hz, 2H), 2.30−2.20 (m, 1H), 2.19−2.10 (m,
1H), 2.06 (s, 1H), 1.93−1.82 (m, 2H), 1.62 (ddq, J = 18.7, 9.3, 5.8,
4.8 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.5, 138.1,
134.4, 129.7, 128.6, 128.4, 126.8, 73.3, 67.5, 52.0, 48.7, 48.5, 34.1
(2C). HRMS (ESI-TOF) m/z: [M + H+] calcd for C14H19ClNO3
284.1048, found 284.1044.
9687
https://doi.org/10.1021/acs.joc.1c00944
J. Org. Chem. 2021, 86, 9682−9691

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1-(1-(3-Chlorophenyl)-2-methoxy-2-oxoethyl)piperidin-4-ylben-
zoate ( 24). Purification with petroleum ether/EtOAc (8:2) as the
eluent; colorless semisolid (295 mg, 76% yield). 1H NMR (400 MHz,
CDCl3) δ 8.05−7.99 (m, 2H), 7.54 (tt, J = 6.9, 1.3 Hz, 1H), 7.48 (d, J
= 1.7 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.36−7.27 (m, 3H), 5.07 (tt, J
= 7.6, 3.8 Hz, 1H), 4.07 (s, 1H), 3.70 (s, 3H), 2.78−2.66 (m, 2H),
2.43 (q, J = 8.4 Hz, 2H), 2.08−1.99 (m, 2H), 1.94−1.83 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.3, 165.7, 138.0, 134.5,
J = 8.5 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 3.94 (s, 1H), 3.67 (s, 3H),
2.35 (m, 4H), 1.57 (quin, J = 5.5 Hz, 4H), 1.43 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ171.9, 134.8, 134.0, 130.1 (2C), 128.6
(2C), 74.1, 52.3 (2C), 51.9, 25.7 (2C), 24.2. HRMS (ESI-TOF) m/z:
[M + H+] calcd for C14H19ClNO2 268.1099, found 268.1097.
Methyl 2-(4-Bromophenyl)-2-(piperidin-1-yl)acetate ( 32). Puri-
fication with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (244 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J
= 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.95 (s, 1H), 3.68 (d, J = 1.1
Hz, 3H), 2.37 (t, J = 5.4 Hz, 4H), 1.59 (quin, J = 5.3 Hz, 4H), 1.47−
1.39 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.7, 135.4,
131.5 (2C), 130.4 (2C), 122.1, 74.1, 52.2 (2C), 51.9, 25.7 (2C), 24.2.
HRMS (ESI-TOF) m/z: [M + H+] calcd for C14H19BrNO2 312.0594,
found 312.0571.
132.8, 130.5, 129.8, 129.5 (2C), 128.7, 128.6, 128.3 (2C), 126.8, 73.3,
70.0, 52.1, 48.4, 48.2, 30.6 (2C). HRMS (ESI-TOF) m/z: [M + H+]
calcd for C21H23ClNO4 388.1310, found 388.1317.
Methyl 2-(3-Chlorophenyl)-2-morpholinoacetate ( 25). Purifica-
tion with petroleum ether/EtOAc (9:1) as the eluent; colorless
1
semisolid (200 mg, 74% yield). H NMR (400 MHz, CDCl3) δ 7.47
(d, J = 2.0 Hz, 1H), 7.36−7.24 (m, 3H), 3.96 (s, 1H), 3.75−3.71 (m,
4H), 3.70 (s, 3H), 2.45 (dd, J = 6.3, 3.2 Hz, 4H). 13C{1H} NMR (101
MHz, CDCl3) δ 171.9, 137.4, 134.5, 129.8, 128.8, 128.7, 126.9, 73.7,
66.7 (2C), 52.1, 51.4 (2C). HRMS (ESI-TOF) m/z: [M + H+] calcd
for C13H17ClNO3 270.0891, found 270.0890.
Methyl 2-(3-Chlorophenyl)-2-(4-ethylpiperazin-1-yl)acetate
( 26). Purification with petroleum ether/EtOAc (8:2) as the eluent;
colorless semisolid (230 mg, 78% yield). 1H NMR (400 MHz,
CDCl3) δ 7.44 (d, J = 1.8 Hz, 1H), 7.30 (dq, J = 5.5, 1.8 Hz, 1H),
7.27−7.24 (m, 2H), 3.95 (s, 1H), 3.67 (s, 3H), 2.69−2.32 (m, 10H),
1.06 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.3,
137.8, 134.5, 129.8, 128.7, 128.6, 127.0, 73.6, 52.4 (3C), 52.2, 52.1,
50.9, 11.8. HRMS (ESI-TOF) m/z: [M + H+] calcd for
C15H22ClN2O2 297.1364, found 297.1352.
Methyl 2-(3-Chlorophenyl)-2-(4-phenylpiperazin-1-yl)acetate
( 27). Purification with petroleum ether/EtOAc (8:2) as the eluent;
colorless semisolid (266 mg, 77% yield). 1H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 1.9 Hz, 1H), 7.37 (dt, J = 6.7, 1.8 Hz, 1H), 7.32
(dt, J = 7.0, 1.6 Hz, 2H), 7.30−7.27 (m, 1H), 7.24 (dd, J = 7.0, 1.8
Hz, 1H), 6.91 (d, J = 1.0 Hz, 1H), 6.90−6.88 (m, 1H), 6.88−6.83 (m,
1H), 4.06 (s, 1H), 3.73 (s, 3H), 3.25−3.20 (m, 4H), 2.66−2.61 (m,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.2, 151.1, 137.7, 134.6,
129.9, 129.1 (2C), 128.8, 128.7, 127.0, 119.8, 116.1 (2C), 73.5, 52.2,
51.0 (2C), 49.0 (2C). HRMS (ESI-TOF) m/z: [M + H+] calcd for
C19H22ClN2O2 345.1364, found 345.1359.
Methyl 2-(2-Chlorophenyl)-2-morpholinoacetate ( 33). Purifica-
tion with petroleum ether/EtOAc (9:1) as the eluent; colorless liquid
(197 mg, 73% yield). H NMR (400 MHz, CDCl3) δ 7.65 (dd, J =
1
7.5, 2.0 Hz, 1H), 7.39 (dd, J = 7.7, 1.7 Hz, 1H), 7.29 (dd, J = 7.4, 5.6
Hz, 1H), 7.25 (dd, J = 7.5, 5.4 Hz, 1H), 4.68 (s, 1H), 3.72 (t, J = 4.7
Hz, 4H), 3.70 (s, 3H), 2.58 (dd, J = 10.6, 5.6 Hz, 2H), 2.52−2.46 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.0, 134.8, 133.1, 129.9,
129.7, 129.3, 127.0, 68.8, 66.8 (2C), 52.0, 51.2 (2C). HRMS (ESI-
TOF) m/z: [M + H+] calcd for C13H17ClNO3 270.0891, found
270.0896.
Methyl 2-(4-Chlorophenyl)-2-morpholinoacetate ( 34). Purifica-
tion with petroleum ether/EtOAc (9:1) as the eluent; colorless liquid
(205 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.5
Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 3.96 (s, 1H), 3.75−3.70 (m, 4H),
3.69 (s, 3H), 2.47−2.42 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3)
δ 171.1, 134.3, 133.9, 130.1 (2C), 128.8 (2C), 73.5, 66.7 (2C), 52.0,
51.4 (2C). HRMS (ESI-TOF) m/z: [M + H+] calcd for
C13H17ClNO3 270.0891, found 270.0893.
Methyl 2-(4-Bromophenyl)-2-morpholinoacetate ( 35). Purifica-
tion with petroleum ether/EtOAc (9:1) as the eluent; colorless liquid
(236 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.5
Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 3.95 (s, 1H), 3.75−3.71 (m, 4H),
3.69 (s, 3H), 2.49−2.41 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3)
δ 171.1, 134.4, 131.8 (2C), 130.4 (2C), 122.6, 73.6, 66.7 (2C), 52.1,
51.5 (2C). HRMS (ESI-TOF) m/z: [M + H+] calcd for
C13H17BrNO3 314.0386, found 314.0376.
Methyl 2-(3-Chlorophenyl)-2-(4-(2,4-dinitrophenyl)piperazin-1-
yl)acetate ( 28). Purification with petroleum ether/EtOAc (1:1) as
1
Methyl 2-Morpholino-2-(4-(tosyloxy)phenyl)acetate ( 36). Puri-
the eluent; yellow solid (mp = 185 °C), (314 mg, 72% yield). H
fication with petroleum ether/EtOAc (7:3) as the eluent; colorless
NMR (400 MHz, CDCl3) δ 8.69 (d, J = 2.7 Hz, 1H), 8.27 (dd, J =
9.3, 2.7 Hz, 1H), 7.48 (s, 1H), 7.35 (q, J = 5.2, 3.7 Hz, 3H), 7.09 (d, J
= 9.3 Hz, 1H), 4.13 (s, 1H), 3.74 (s, 3H), 3.36−3.30 (m, 4H), 2.71−
2.65 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.7, 149.1,
138.7, 138.4, 136.8, 134.8, 130.0, 129.0, 128.8, 128.3, 127.0, 123.6,
119.3, 72.6, 52.4, 50.4 (2C), 50.1 (2C). HRMS (ESI-TOF) m/z: [M
+ H+] calcd for C19H20ClN4O6 435.1066, found 435.0993.
1
semisolid (296 mg, 73% yield). H NMR (400 MHz, CDCl3) δ 7.70
(d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H),
6.97 (d, J = 8.7 Hz, 2H), 3.96 (s, 1H), 3.71−3.68 (m, 4H), 3.67 (s,
3H), 2.44 (s, 3H), 2.43−2.34 (m, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 171.1, 149.6, 145.5, 134.1, 132.4, 130.1 (2C), 129.7 (2C),
128.4 (2C), 122.5 (2C), 73.4, 66.6 (2C), 52.1, 51.4 (2C), 21.7.
HRMS (ESI-TOF) m/z: [M + H+] calcd for C20H24NO6S 406.1319,
found 406.1326.
Methyl-2-phenyl-2-(piperidin-1-yl)acetate ( 29). Purification
with petroleum ether/EtOAc (9:1) as the eluent; colorless liquid
(180 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.42 (dt, J = 8.3,
2.3 Hz, 2H), 7.35−7.28 (m, 3H), 3.97 (s, 1H), 3.67 (s, 3H), 2.38 (m,
4H), 1.59 (quin, J = 5.5 Hz, 4H), 1.42 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ172.3, 136.2, 128.8, 128.4, 128.1, 75.0, 52.4 (2C),
51.8, 25.7 (2C), 24.3. HRMS (ESI-TOF) m/z: [M + H+] calcd for
C14H20NO2 234.1489, found 234.1489.
Methyl 2-(2-Chlorophenyl)-2-(piperidin-1-yl)acetate ( 30). Puri-
fication with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (188 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.65 (dd,
J = 7.7, 1.9 Hz, 1H), 7.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.25 (td, J = 7.5,
1.5 Hz, 1H), 7.19 (td, J = 7.6, 1.9 Hz, 1H), 4.60 (s, 1H), 3.66 (s, 3H),
2.50 (dt, J = 10.6, 5.2 Hz, 2H), 2.39 (dt, J = 10.9, 5.4 Hz, 2H), 1.57
(quin, J = 5.2 Hz, 4H), 1.42 (quin, J = 5.9 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ171.4, 134.5, 134.1, 129.9, 129.5, 128.9, 126.8,
69.5, 52.1 (2C), 51.8, 25.9 (2C), 24.2. HRMS (ESI-TOF) m/z: [M +
H+] calcd for C14H19ClNO2 268.1099, found 268.1100.
Methyl 2-(3-Chlorophenyl)-2-(4-((4-chlorophenyl)(phenyl)-
methyl)piperazin-1-yl)acetate ( 37). Purification with petroleum
ether/EtOAc (8:2) as the eluent; colorless semisolid (282 mg, 60%
1
yield). H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.38−7.31 (m,
4H), 7.31−7.23 (m, 5H), 7.23−7.14 (m, 3H), 4.23 (s, 1H), 4.00 (s,
1H), 3.68 (s, 3H), 2.46 (m, 8H). 13C{1H} NMR (101 MHz, CDCl3)
δ 171.2, 137.7, 134.5, 132.5, 129.7, 129.2 (3C), 128.8, 128.6 (3C),
128.5, 127.8 (3C), 127.2, 126.9, 75.2, 73.4, 52.1, 51.5 (2C), 51.1
(2C). HRMS (ESI-TOF) m/z: [M + H+] calcd for C26H27Cl2N2O2
469.1444, found 469.1453.
Controlled Experiments. Electrolysis with a constant current
condition (8 mA) was carried out using a graphite plate as the anode
and a copper plate as the cathode for 12 h through an undivided
reaction cell equipped with a stirring bar and methyl 2-(3-
chlorophenyl)acetate 1 (184 mg, 1.0 mmol, 1.0 equiv), pyrrolidine
2 (71 mg, 1.0 mmol, 1.0 equiv), KI (83 mg, 0.5 mmol, 0.5 equiv), and
LiClO4 (106 mg, 1.0 mmol, 1.0 equiv) dissolved in 10.0 mL of
CH3CN. The reaction progress was monitored by TLC. Using a
reduced amount of amine 2 (1.0 equiv) under standard conditions, we
Methyl 2-(4-Chlorophenyl)-2-(piperidin-1-yl)acetate ( 31). Puri-
fication with petroleum ether/EtOAc (9:1) as the eluent; colorless
liquid (212 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ δ 7.37 (d,
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observed the formation of α-iodo-ester 38 (139 mg, 45% yield) and
expected product 3 (<10% yield), after purification.
(10.0 mL). The organic layer was separated and washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Purification by column chromatography using petroleum
ether/EtOAc (8:2) as the eluent afforded 39 as a transparent oil (114
mg, 58% after three steps). 1H NMR (400 MHz, CDCl3) δ 7.33−7.29
(m, 3H), 7.20 (d, J = 10.1 Hz, 1H), 4.64 (dd, J = 9.8, 3.9 Hz, 1H),
2.70 (dd, J = 13.4, 9.8 Hz, 1H), 2.58 (dd, J = 9.9, 5.8 Hz, 2H), 2.52
(dd, J = 13.4, 3.9 Hz, 1H), 2.49−2.42 (m, 2H), 1.62 (m, 4H), 1.46
(quin, J = 5.7 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.9,
134.4, 129.8, 128.1, 126.9, 124.9, 65.5, 62.5, 54.8 (2C), 25.8 (2C),
24.2. HRMS (ESI-TOF) m/z: [M + H+] calcd for C13H18ClN4
265.1215, found 265.1219.
Methyl 2-Iodo-2-phenylacetate ( 38). Purification with petro-
leum ether/EtOAc (9:1) as the eluent; colorless liquid (139 mg, 45%
yield). 1H NMR (400 MHz, CDCl3) δ 7.49−7.46 (m, 1H), 7.38−7.34
(m, 1H), 7.31−7.26 (m, 2H), 4.32 (s, 1H), 3.46 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 171.1, 137.9, 134.6, 130.0, 128.5, 128.4,
126.6, 54.4, 52.3. HRMS (ESI-TOF) m/z: [M + Na+] calcd for
C9H8IClO2Na 332.9150, found 332.9128.
To a stirred solution of 38 (130 mg, 0.4 mmol, 1.0 equiv) and 2
(71 mg, 1.0 mmol, 2.5 equiv) in CH3CN (4.0 mL) was added Et3N
(61 mg, 0.6 mmol, 1.5 equiv) and left for 3 h at room temperature.
Once 38 disappeared from TLC, the reaction mixture was diluted
with brine (4.0 mL) and extracted with ethyl acetate (10.0 mL). The
combined organic layer was dried over anhydrous Na2SO4,
concentrated, and purified to afford 3 (90 mg, 89%) as a pale-yellow
liquid.
Reaction in the Presence of Radical Inhibitors (TEMPO/
BHT). To a 10 mL dried undivided reaction cell equipped with a
stirring bar were added methyl 2-(3-chlorophenyl) acetate 1 (100 mg,
0.54 mmol, 1.0 equiv), pyrrolidine 2 (114 mg, 1.6 mmol, 3.0 equiv),
KI (45 mg, 0.27 mmol, 0.5 equiv), TEMPO (211 mg, 1.35 mmol, 2.5
equiv) or BHT (297 mg, 1.35 mmol, 2.5 equiv), and LiClO4 (57 mg,
1.0 mmol, 1.0 equiv) dissolved in 10.0 mL of CH3CN. The combined
reaction mixture was electrolyzed under standard conditions. The
trace of product 3 was observed (TEMPO) or not observed (BHT)
on TLC.
Gram-Scale Synthesis of 22. A 100 mL three-neck round-
bottom flask (as an undivided cell) was equipped with a graphite plate
as the anode and a copper plate as the cathode, which was connected
to a DC regulated power supply. To the cell were added methyl 2-(3-
chlorophenyl) acetate 1 (1.0 g, 5.43 mmol, 1.0 equiv), piperidine
(1.38 g, 16.25 mmol, 3.0 equiv), KI (0.45 g, 2.71 mmol, 0.5 equiv),
and LiClO4 (0.58 g, 5.43 mmol, 1.0 equiv) dissolved in 40.0 mL of
CH3CN. The mixture was electrolyzed under constant current
conditions (8 mA) under a N2 atmosphere at room temperature
while stirring. The reaction was monitored by TLC. Electrodes were
washed with ethyl acetate (10 mL); when the reaction was finished,
the solvent was removed under reduced pressure. The residue was
poured into a saturated aqueous Na2S2O3 (20.0 mL) and extracted
with ethyl acetate (2 × 20.0 mL). The combined organic layer was
separated, washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude cycloadduct was
purified by column chromatography on silica gel using petroleum
ether/EtOAc (9:1), affording pure 22 (1.30 g, 90%).
Benzo[d][1,3]dioxol-5-ylmethyl-2-(2-chlorophenyl)-2-(pyrrolidin-
1-yl)acetate ( 40). To a stirred solution of the ester 33 (100 mg,
0.37 mmol, 1.0 equiv) in THF/H2O (2:1, 6.0 mL) was added LiOH·
H2O (47 mg, 1.1 mmol, 3.0 equiv) at rt and further stirred for 8−10
h. The reaction mixture was evaporated to dryness, and the resulting
solid crude material was taken forward without purification. This
crude solid mass was taken in DMF (4.0 mL), N,N-diisopropylethyl-
amine (DIPEA) was added (70 μL, 0.4 mmol, 1.1 equiv), and
subsequently, EDC·HCl (1-ethyl-3(3-dimethylaminopropyl)-carbo-
diimidehydrochloride) (77 mg, 0.4 mmol, 1.1 equiv), 1-hydrox-
ybenzotriazole (HOBt) (54 mg, 0.4 mmol, 1.1 equiv), and diethyl
amine (35 mg, 0.48 mmol, 1.3 equiv) were added at rt and cooled to 0
°C. The reaction mixture was further stirred at rt for 12 h, before
quenching with H2O (5.0 mL) and being stirred with EtOAc (10
mL). The organic layer was separated, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Purification by column
chromatography using petroleum ether/EtOAc (7:3) afforded 40 (87
1
mg, 76% after two steps) as a colorless liquid. H NMR (400 MHz,
CDCl3) δ 7.68 (dd, J = 7.6, 2.0 Hz, 1H), 7.30 (dd, J = 7.7, 1.6 Hz,
1H), 7.22−7.12 (m, 2H), 4.72 (s, 1H), 3.33 (m, 2H), 3.18 (m, 2H),
2.56−2.45 (m, 2H), 2.41 (m, 2H), 1.56−1.43 (m, 4H), 1.34 (quin, J
= 5.8 Hz, 2H), 0.99 (q, J = 7.1 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 169.7, 134.4, 133.9, 131.2, 129.1, 128.8, 126.8, 65.6, 51.9
(2C), 41.2, 40.4, 25.9 (2C), 24.3, 14.1, 12.5. HRMS (ESI-TOF) m/z:
[M + H+] calcd for C17H26ClN2O 309.1728, found 309.1728.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00944.
■
sı
Optimization table, NMR spectra (PDF)
1-(2-Azido-1-(3-chlorophenyl)ethyl)piperidine ( 39). To a stirred
solution of 22 (200 mg, 0.74 mmol, 1.0 equiv) in dry tetrahydrofuran
(THF) (10.0 mL) at 0 °C was added LiAlH4 (93 mg, 2.24 mmol, 3.0
equiv) portionwise over 10 min. The combined mixture was stirred at
room temperature for 4 h before cooling to 0 °C and quenched slowly
with aqueous NH4Cl solution (10.0 mL). The reaction mixture was
further stirred with EtOAc (30.0 mL). The solid mass was removed
by filtration, and the aqueous layer was again extracted with EtOAc
(10.0 mL). The combined organic mixture was concentrated under
reduced pressure, and crude alcohol was used further without
purification.
To a stirred solution of crude alcohol (200 mg, crude weight), Et3N
(146 μL, 1.05 mmol, 1.5 equiv), and DMAP (9.0 mg, 0.07 mmol, 0.1
equiv) in CH2Cl2 (5.0 mL), in a 25 mL round-bottom flask, was
added a solution of TsCl (147 mg, 0.77 mmol, 1.1 equiv) in CH2Cl2
(3.0 mL) at 0 °C under a N2 atmosphere. The resulting mixture was
further stirred at rt for 10 h before being quenched with saturated
aqueous NaHCO3 (8.0 mL) and stirred with additional CH2Cl2 (10.0
mL). The combined organic layer was separated, dried over
anhydrous Na2SO4, and concentrated under reduced pressure, and
the crude tosyl product was used further without purification.
To a solution of crude tosylate (315 mg, crude weight) in
dimethylformamide (DMF) (4.0 mL) was added NaN3 (98 mg, 1.5
mmol, 2.0 equiv) and heated at 65 °C for 8 h. The mixture was cooled
to room temperature and stirred between H2O (4.0 mL) and EtOAc
AUTHOR INFORMATION
Corresponding Author
■
Indresh Kumar − Department of Chemistry, Birla Institute of
Technology and Science, Pilani 333031, Rajasthan, India;
orcid.org/0000-0003-4621-1236;
Email: indresh.chemistry@gmail.com, indresh.kumar@
pilani.bits-pilani.ac.in
Authors
Yadav Kacharu Nagare − Department of Chemistry, Birla
Institute of Technology and Science, Pilani 333031,
Rajasthan, India
Imtiyaz Ahmad Shah − Department of Chemistry, Birla
Institute of Technology and Science, Pilani 333031,
Rajasthan, India
Jyothi Yadav − Department of Chemistry, Birla Institute of
Technology and Science, Pilani 333031, Rajasthan, India
Amol Prakash Pawar − Department of Chemistry, Birla
Institute of Technology and Science, Pilani 333031,
Rajasthan, India
Rahul Choudhary − Praveen Laboratories Pvt. Ltd., Surat
394304, Gujarat, India
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(5) (a) Evans, R. E.; Zbieg, J. R.; Zhu, S.; Li, W.; Macmillan, D. W.
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Carbonyls with Functionalized Amines: A One-Step Synthesis of
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Pankaj Chauhan − Department of Chemistry, Indian Institute
of Technology Jammu, Jammu 181221, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00944
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by DST-SERB (CRG/
2020/003424). Y.K.N. thanks SERB, New Delhi, and Praveen
Laboratories Pvt. Ltd., Surat, collectively, for the Prime
Minister’s Fellowship. I.A.S., J.Y., and A.P.P. thank BITS Pilani
for Research Fellowships. The authors thank DST-FIST (SR/
FST/CSI-270/2015) for the HRMS facility to the Department
of Chemistry.
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