Photocatalytic carbocarboxylation of styrenes with CO2for the synthesis of γ-aminobutyric esters

Article abstract of DOI:10.1039/d1ob00866h

Metal-free photoredox-catalyzed carbocarboxylation of various styrenes with carbon dioxide (CO₂) and amines to obtain γ-aminobutyric ester derivatives has been developed (up to 91% yield, 36 examples). The radical anion of (2,3,4,6)-3-benzyl-2,4,5,6-tetra(9H-carbazol-9-yl)benzonitrile (4CzBnBN) possessing a high reduction potential (?1.72 Vvs.saturated calomel electrode (SCE)) easily reduces both electron-donating and electron-withdrawing group-substituted styrenes.

Full text of DOI:10.1039/d1ob00866h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Photocatalytic carbocarboxylation of styrenes
with CO2 for the synthesis of γ-aminobutyric
esters†
Cite this: Org. Biomol. Chem., 2021,
19, 6301
Hyungwoo Hahm, a Jiyun Kim,a Jeong Yup Ryoo,a Min Su Han a and
a,b
Sukwon Hong
*
Metal-free photoredox-catalyzed carbocarboxylation of various styrenes with carbon dioxide (CO2) and
amines to obtain γ-aminobutyric ester derivatives has been developed (up to 91% yield, 36 examples). The
radical anion of (2,3,4,6)-3-benzyl-2,4,5,6-tetra(9H-carbazol-9-yl)benzonitrile (4CzBnBN) possessing a
high reduction potential (−1.72 V vs. saturated calomel electrode (SCE)) easily reduces both electron-
donating and electron-withdrawing group-substituted styrenes.
Received 4th May 2021,
Accepted 16th June 2021
DOI: 10.1039/d1ob00866h
rsc.li/obc
tion,7c phosphonocarboxylation7e and carboarylation7f of
alkenes with CO2 and various radical sources.
Introduction
The synthesis of carboxylic acids through direct carboxylation
γ-Aminobutyric acid derivatives have important applications
using carbon dioxide (CO2) has received much attention as the in the pharmaceutical industry9 and in peptide chemistry.10
products are important in medicinal chemistry applications Among the photocatalytic syntheses of γ-aminobutyric acids,
and in the preparation of fine chemicals.1 Moreover, this syn- the photocatalytic addition of α-aminoalkyl radicals to unsatu-
thetic route is a more potentially attractive pathway than the rated bonds, such as α,β-unsaturated carbonyl compounds,
traditional process that involves a multistep formylation/oxi- has been widely studied.11 However, the photoredox-catalyzed
dation process.2 Due to the high thermodynamic stability and difunctionalization of alkenes using CO2 to obtain γ-amino
low reactivity of CO2, a variety of carboxylations through tran- acids is still rare. Recently, Wu and Xi and Chen independently
sition metal catalysis have been developed.3 However, these reported the visible-light-mediated carbocarboxylation of elec-
reactions require stoichiometric metal reductants4 or organo- tron-deficient alkenes containing nitrile (–CN), ester (CO2R),
metallic reagents.5
and amide (CONHR) groups with CO2 and alkyl amine radical
Over the last decade, sustainable photoredox catalysis sources in the presence of 1,2,3,5-tetrakis-(carbazol-9-yl)-4,6-
occurring under mild reaction conditions has been extensively dicyanobenzene (4CzIPN) and hydrogen atom transfer (HAT)
studied as an important strategy in direct carboxylation for C– catalysts or LiCl to obtain γ-aminobutyric acid derivatives
C bond formation with CO2.6 In particular, the photocatalytic (Scheme 1a).7c,g Very recently, Yu and Cheng and Sun indepen-
difunctionalization of unsaturated hydrocarbons using CO2 dently developed the carbocarboxylation of activated alkenes
has attracted much attention as a useful method for obtaining using α-amino acids and peptide derivatives with in situ gener-
high value-added carboxylic acid derivatives.7 By using this ated CO2 for the synthesis of valuable γ-aminobutyric acids
strategy, both carboxylic acid and another functional group are (Scheme 1a).7i,j We recently reported a photocatalytic carbocar-
incorporated into unsaturated hydrocarbons in a single step boxylation of allenes with CO2 and amines (Scheme 1a).7l
with high atom- and step-economic efficiency.8 Recently, the However, the photocatalytic difunctionalization of electron-
efforts of several research groups have resulted in great pro- rich alkenes with a high reduction potential remains a
gress in photocatalytic difunctionalization such as problem in this area. We envision that the expansion of the
carbocarboxylation,7a,c,g,i,j thiocarboxylation,7b silacarboxyla- substrate scope of alkenes by using a photocatalyst with a high
reduction potential, such as (2,3,4,6)-3-benzyl-2,4,5,6-tetra(9H-
carbazol-9-yl)benzonitrile (4CzBnBN), could be a general syn-
thetic method to obtain γ-aminobutyric acids.12 Herein, we
aDepartment of Chemistry, Gwangju Institute of Science and Technology, 123
Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea.
report the visible-light-mediated carbocarboxylation of elec-
E-mail: shong@gist.ac.kr
tron-rich and electron-deficient alkenes with CO2 and N,N-
bSchool of Materials Science and Engineering, Gwangju Institute of Science and
dimethyl anilines using 4CzBnBN for the synthesis of
Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 61005, Republic of Korea
γ-aminobutyric esters (Scheme 1b). This reaction has a broad
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
substrate scope and can be performed under mild conditions.
D1OB00866H
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6301–6312 | 6301

View Article Online
Paper
Organic & Biomolecular Chemistry
radical source in the presence of 5 mol% of the 4CzBnBN
photocatalyst while using N,N-dimethylformamide (DMF) as
the solvent and K2HPO4 as the base under irradiation with a
15 W blue light-emitting diode (LED) at room temperature
with CO2 at atmospheric pressure (Table 1 and Table S1†). In
the initial catalyst screening, 4CzBnBN showed the best reactiv-
ity with a 64% yield (entry 1, Table 1). 3aa was not obtained
using other photocatalysts such as 4CzIPN, [Ir(dF(CF3)
ppy)2(dtbpy)]PF6, and Ir(ppy)3 instead of 4CzBnBN (entries
2–4, Table 1). Using [Ir(ppy)2(dtbpy)]PF6 resulted in a lower
yield (entry 5, Table 1). The 4-fluorobenzyl radical (−1.50 V vs.
SCE)13 can be easily reduced by 4CzBnBN. Using 3 mol% of
4CzBnBN, the reaction yield slightly decreased (entry 6,
Table 1). Next, we investigated some other bases such as KOH,
K2CO3, KOCOCF3, KHCO3, and KOAc. The use of these bases
did not improve the yields (entries 7–11, Table 1). Next, using
other solvents such as N,N-dimethylacetamide (DMA),
1-methyl-2-pyrrolidinone (NMP), and dimethyl sulfoxide
(DMSO) reduced the yield of 3aa (entries 12–14, Table 1). In
the absence of 4CzBnBN, light, or CO2, no desired product was
detected (entries 15–17, Table 1). We carried out the carbocar-
boxylation with 3 equivalents of 1a (entry 18, Table 1 and
Table 1 Optimization of the carbocarboxylation of styrenesa
Entry
Deviation from the standard conditions
Yieldb
1
2
3
4
None
64%
<1%
<1%
<1%
10%
56%
37%
35%
23%
51%
50%
60%
61%
36%
<1%
<1%
<1%
9%
4CzIPN instead of 4CzBnBN
[Ir(dF(CF3)ppy)2(dtbpy)]PF6 instead of 4CzBnBN
Ir(ppy)3 instead of 4CzBnBN
[Ir(ppy)2(dtbpy)]PF6 instead of 4CzBnBN
4CzBnBN
KOH instead of K2HPO4
K2CO3 instead of K2HPO4
KOCOCF3 instead of K2HPO4
KHCO3 instead of K2HPO4
KOAc instead of K2HPO4
DMA instead of DMF
NMP instead of DMF
DMSO instead of DMF
No light
5
6c
7
Scheme 1 Synthesis of γ-aminobutyric acids via photocatalytic carbo-
carboxylation with CO2.
8
9
10
11
12
13
14
15
16
17
18d
Results and discussion
The radical anion of 4CzBnBN has a high reduction potential
(−1.72 V vs. SCE). Since electron-neutral and electron-donating
group-substituted benzyl radicals have high reduction poten-
tials (−1.43 V vs. SCE for the H benzyl radical analog and
−1.62 V vs. SCE for the p-Me benzyl radical analog), a photo-
catalyst with a higher potential is required for reduction
(Schemes S1 and S2†).13
No 4CzBnBN
N2 instead of CO2
la (3 equiv.), 2a (1 equiv.)
a Reaction conditions: (1) 0.2 mmol 1a, 0.6 mmol 2a, 0.6 mmol base, 1
or 5 mol% photocatalyst, solvent (2 mL), and CO2 (closed), Kessil blue
LED (15 W), 6 h and (2) TMSCHN2 2 M in Et2O (0.2 mL), Et2O (8 mL),
MeOH (2 mL), 1 h. b Isolated yield. c 3 mol%. d (1) 0.6 mmol 1a,
0.2 mmol 2a, 0.2 mmol K2HPO4, 5 mol% 4CzBnBN, DMF (2 mL), CO2
(closed), 15 W blue LED, 6 h, and (2) TMSCHN2 2 M in Et2O (0.2 mL),
Et2O (8 mL), MeOH (2 mL), 1 h.
We initially investigated the reaction using 4-fluorostyrene
as a model substrate with 4,N,N-trimethylaniline (2a) as a
6302 | Org. Biomol. Chem., 2021, 19, 6301–6312
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
Table S3†). It is essential to use 3 equivalents of amine in this substituted styrene derivatives at the meta-position of the
reaction.14
phenyl ring have good reactivity (3oa–qa). Additionally, 1,1-di-
Encouraged by these results, we investigated the substrate substituted styrenes could also be used to obtain products
scope of a wider range of styrenes (Scheme 2). Under the opti- bearing quaternary carbon centers in good yields (3ra and
mized reaction conditions, the styrene derivatives having an 3sa). We then proceeded to test a variety of anilines with
electron-donating substituent at the para position of the styrene (Scheme 3). Neutral, electron-donating, or electron-
phenyl ring were effective in affording the desired products in deficient groups bearing anilines such as N,N-dimethylaniline,
moderate to good yields, except for p-methoxystyrene that 3-N,N-trimethylaniline, 3,5-N,N-tetramethylaniline, 4-chloro-N,
showed a high reduction potential (−1.75 V vs. SCE) (3ba–fa).13 N-dimethylaniline and 4-bromo-N,N-dimethylaniline showed
Methoxy (–OMe)- or methyl (–Me)-substituted styrene deriva- good reactivity (3fb–fd, 3ff and 3fg). When 4-methoxy- and
tives at the ortho- or meta position of the phenyl ring showed 4-fluoro-N,N-dimethylaniline were tested, a significantly low
good reactivity (3ga–ja). Styrene derivatives having electron- yield was observed (3fe and 3fh). Other aromatic amines, such
withdrawing groups such as trifluoromethyl (–CF3), cyano as methyldiphenylamine, 9-methyl-9H-carbazole and 1-phenyl-
(–CN), bromo (–Br), or chloro (–Cl)-groups at the para position pyrrolidine, showed good reactivity (3fi–fk). Next, we also inves-
of the phenyl ring were effective in providing the desired pro- tigated various anilines with 4-trifluoromethylstyrene to
ducts in moderate to good yields (3ka–na). The CF3-, Br-, or Cl- confirm that this reaction is a general method for the syn-
thesis of γ-aminobutyric acids. Neutral, electron-donating, or
Scheme 2 Styrene substrate scope of the carbocarboxylation. Reaction
conditions: (1) 1 (0.2 mmol), 2a (0.6 mmol), 4CzBnBN (5 mol%), and
Scheme 3 Amine scope of the carbocarboxylation. Reaction con-
ditions: Conditions: (1) 1f or 1k (0.2 mmol), 2 (0.6 mmol), 4CzBnBN
(5 mol%), and K2HPO4(0.6 mmol) in DMF (2 mL), CO2 (closed), 6 h and
(2) TMSCHN2 2 M in Et2O (0.2 mL), Et2O (8 mL), and MeOH (2 mL).
aIsolated yield of the hydroaminomethylated side-product.
K2HPO4 (0.6 mmol) in DMF (2 mL), CO2 (closed), 6 h and (2) TMSCHN2
2
M in Et2O (0.2 mL), Et2O (8 mL), and MeOH (2 mL). aIsolated yield of the
hydroaminomethylated side-product.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6301–6312 | 6303

View Article Online
Paper
Organic & Biomolecular Chemistry
electron-deficient groups bearing anilines showed good reac-
tivity (3kb–kh). Unfortunately, the use of aliphatic amines,
such as N,N-dimethylallyamine, N,N-dimethylbenzylamine,
and N,N-dicyclohexylmethylamine, did not afford the corres-
ponding products.
To gain insight into the mechanism of the carbocarboxyla-
tion, additional experiments were performed (Fig. 1). When the
radical scavenger 2,2,6,6-tetramethyl-piperidinyloxyl (TEMPO)
was used as an additive for this reaction, the formation of 3fa
was inhibited and TEMPO-trapping products were detected by
HRMS (Fig. S2†). This result shows that the carbocarboxylation
proceeds through the radical pathway.
Scheme 4 Proposed mechanism.
An isotope labelling study with D2O instead of CO2 indi-
cates that benzyl anion species are present in the catalytic
cycle (Fig. S3†). Stern–Volmer quenching experiments confirm
the kinetic preference for the single-electron oxidation of 2a
[Ep = +0.74 V vs. SCE] over 1f by light-activated 4CzBnBN
[E1/2(P*/P−) = +1.21 V vs. SCE]12a (Fig. S4 and S5†).
Based on the experimental results and related references,
the probable mechanism of the regioselective carbocarboxyla-
tion is proposed, as outlined in Scheme 4 (Scheme S3, Fig. S2
and S3†). The α-aminomethyl radical (2′), which is produced
by photoexcited 4CzBnBN and a base, undergoes an addition
reaction with styrene to give the radical intermediate A, which
Scheme 5 Gram scale reaction and synthetic application.
is further reduced to carbanion B via single electron transfer
(SET).14 Since 4CzBnBN has a high reduction potential, the H
benzyl radical analog (−1.43 V vs. SCE) and the p-Me benzyl
radical analog (−1.62 V vs. SCE) might be reduced to inter-
mediate B (Schemes S1 and S2†).13,15 Subsequently, intermedi-
ate B attack CO2, affording the desired product γ-aminobutyric
ester after treatment with TMSCHN2, and 4CzBnBN can be
regenerated in the catalytic cycle.
Functionalized γ-lactams are often of biological and medic-
inal interest.16 To demonstrate the utility of this synthetic
methodology, we conducted a gram scale reaction to obtain
γ-aminobutyric ester. The functionalized γ-aminobutyric ester
3ke was then deprotected readily by periodic acid followed by
lactamization in the presence of trimethylamine to afford func-
tionalized γ-lactam 5 (Scheme 5).17
Conclusions
In summary, we developed a redox-neutral synthetic method to
obtain various γ-aminobutyric esters via the photoredox-cata-
lyzed difunctionalization of various styrenes with N,N-di-
methylaniline derivatives. The reactions proceed under atmos-
pheric pressure of CO2 without the need for stoichiometric
amounts of reductants. 4CzBnBN is an efficient photocatalyst
for the regioselective carbocarboxylation of various electron-
donating and electron-withdrawing group-substituted styrenes
with CO2. The development of a new methodology for the syn-
thesis of γ-aminobutyric esters is currently ongoing.
Experimental
General information
All reactions were performed in flame-dried glassware under
an argon atmosphere by using standard Schlenk techniques or
Fig. 1 Mechanistic studies.
6304 | Org. Biomol. Chem., 2021, 19, 6301–6312
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
a glove box. Concentration of solutions was carried out by nique. DMF (2 mL), styrene derivatives (0.2 mmol) and N,N-di-
using a rotary evaporator with a water aspirator and was gener- methylaniline derivatives (0.6 mmol) were added under a flow
ally followed by the removal of residual solvents on a vacuum of CO2 and the Schlenk tube was closed. Then, the reaction
line maintained at 0.1–1 Torr. Unless otherwise stated, all was conducted in the Schlenk tube irradiated with Kessil LED
commercial reagents and solvents were used without light (A80, Tuna Blue, 15 W; the distance between the Schlenk
additional purification. Nuclear magnetic resonance (NMR) tube and the LED was about 6–8 cm) for 6 h at room tempera-
spectra were recorded by using a JEOL spectrometer, operated ture (28–32 °C). The reaction was cooled using a fan. After the
1
at 400 MHz for H NMR, 100 MHz for 13C NMR, and 376 MHz completion of the reaction, it was quenched with 1 M HCl
1
for 19F NMR spectra. All chemical shifts for H and 13C NMR (2 mL) and extracted with ethyl acetate (5 mL × 3). The com-
spectroscopy were referenced to the residual solvent peak from bined organic phase was dried using MgSO4 and filtered, and
CDCl3 (1H: δ = 7.26 ppm; 13C: δ = 77.16 ppm). High-resolution ethyl acetate was evaporated. The crude product was dissolved
mass spectra (HRMS) were recorded on a JEOL JMS-700 in diethyl ether (8 mL) and MeOH (2 mL) at 0 °C. Then, tri-
MStation mass spectrometer. The fluorescence spectra were methylsilyldiazomethane (2 M in ether, 0.2 mL) was added
recorded using a fluorescence spectrophotometer. Analytical dropwise to the mixture. The resulting mixture was stirred at
thin layer chromatography (TLC) was performed on pre-coated room temperature for 1 h. The solvent in the crude material
silica gel 60 F254 plates. Visualization on TLC was achieved was evaporated and the crude material was separated by silica
using UV light (254 nm). Flash column chromatography was gel column chromatography (5–10% ethyl acetate/n-hexane).
performed on silica gel (230–400 mesh). Tetrahydrofuran,
Methyl 2-(4-fluorophenyl)-4-(methyl(p-tolyl)amino)butano-
diethyl ether, dichloromethane, and dimethylformamide were ate (3aa). The crude material was separated by silica gel
dried under a positive pressure of dry nitrogen by using a column chromatography (5% ethyl acetate/n-hexane) to give
1
J. C. Meyer solvent purification system. N-Methyl-2-pyrroli- the desired product as a colorless oil (40.4 mg, 64%). H NMR
done, dimethyl sulfoxide, and N,N-dimethylacetamide were (400 MHz, CDCl3) δ 7.30–7.27 (m, 2H), 7.05 (d, J = 8.7 Hz, 2H),
distilled from calcium hydride. All other chemicals were pur- 7.04–7.01 (m, 2H), 6.63 (d, J = 8 Hz, 2H), 3.66 (s, 3H), 3.56 (t, J
chased from Sigma-Aldrich Co., TCI, or Alfa Aesar and were = 7.6 Hz, 1H), 3.31–3.17 (m, 2H), 2.86 (s, 3H), 2.36 (dtd, J = 6.5,
used as received without further purification.
5.5, 1.9 Hz, 1H), 2.26 (s, 3H), 1.99 (dtd, J = 6.3, 5.8, 1.4 Hz, 1H).
General procedure for the synthesis of styrenes (1d, 1g, 1h, 13C NMR (100 MHz, CDCl3) δ 174.1, 174.1, 163.5, 161.0, 134.5,
1j, 1r).18 The mixture of benzaldehyde derivatives (5 mmol), 134.5, 129.8, 129.7, 129.6, 129.6, 115.8, 115.8, 115.6, 113.1,
methyltriphenylphosphonium bromide (8 mmol), potassium 52.3, 51.1, 48.4, 38.7, 30.4, 20.3. 19F NMR (376 MHz, CDCl3) δ
+
carbonate (8 mmol) and anhydrous 1,4-dioxane (5 mL) was −115.0. HRMS (ESI) m/z: [M + H]+ calcd for C19H23FNO2 ,
added to a Schlenk flask under an argon atmosphere and 316.1707; found: 316.1707. IR (ν) = 2920, 2859, 1733, 1616,
heated to reflux for 24 h. The reaction was quenched with 1508, 1435, 1348, 1266, 1222, 1155, 1117, 1044, 959, 834, 803,
water and the aqueous layer was extracted using diethyl ether. 748, 698 cm−1
.
The combined organic phase was dried using MgSO4 and fil-
Methyl 4-(methyl(p-tolyl)amino)-2-(p-tolyl)butanoate (3ba).
tered, and diethyl ether was evaporated. The oil mixture was The crude material was separated by silica gel column chrom-
separated by silica gel column chromatography (diethyl ether/ atography (5% ethyl acetate/n-hexane) to give the desired
1
n-hexane = 1 : 40) and the desired compounds, styrene deriva- product as a colorless oil (36.7 mg, 59%). H NMR (400 MHz,
tives, were obtained as a colorless oil.
CDCl3) δ 7.21 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.03
General procedure for the synthesis of N,N-dimethylanilines (d, J = 8.5 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 3.66 (s, 3H), 3.57 (t,
(2e, 2f, 2h).19 Iodomethane (22 mmol, 1.37 mL, 2.2 equiv.) was J = 7.6 Hz, 1H), 3.29–3.122 (m, 2H), 2.86 (s, 3H), 2.41–2.32 (m,
added dropwise to a stirred suspension of the corresponding 1H), 2.35 (s, 3H), 2.26 (s, 3H), 2.05–1.96 (m, 1H). 13C NMR
aniline (20 mmol,
1 equiv.) and potassium carbonate (100 MHz, CDCl3) δ 174.4, 147.4, 137.2, 135.8, 129.8, 129.5,
(30 mmol, 4.15 g, 3 equiv.) in 30 mL of N,N-dimethyl- 127.9, 125.8, 113.0, 52.2, 51.2, 48.8, 38.6, 30.3, 21.2, 20.3.
formamide (DMF). The reaction mixture was stirred at room HRMS (ESI) m/z: [M + H]+ calcd for C20H26NO2+, 312.1958;
temperature for 16 h, and then diluted with water (50 mL). found: 312.1959. IR (ν) = 2935, 2923, 1731, 1617, 1518, 1449,
The solution was extracted with diethyl ether (3 × 30 mL) and 1348, 1265, 1209, 1161, 1043, 959, 803, 734, 702 cm−1
.
the combined organic phase was washed with water. The
Methyl 2-(4-(tert-butyl)phenyl)-4-(methyl(p-tolyl)amino)butano-
organic phase was dried using MgSO4 and filtered, and diethyl ate (3ca). The crude material was separated by silica gel
ether was evaporated. The mixture was separated by silica gel column chromatography (5% ethyl acetate/n-hexane) to give
1
column chromatography (ethyl acetate/hexanes = 1 : 10) and the desired product as a colorless oil (48.1 mg, 68%). H NMR
the desired compounds, N,N-dimethylaniline derivatives, were (400 MHz, CDCl3) δ 7.34 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.3 Hz,
obtained as a pale yellow powder.
2H), 7.01 (d, J = 8.6, 2H), 6.58 (d, J = 8.5 Hz, 2H), 3.66 (s, 3H),
3.65 (t, J = 7.6 Hz, 1H), 3.24 (m, 2H), 2.86 (s, 3H), 2.37 (m, 1H),
2.25 (s, 3H), 1.99 (m, 1H), 1.31 (s, 9H). 13C NMR (100 MHz,
General procedure for carbocarboxylation of styrenes
A 10 mL Schlenk tube was charged with 4CzBnBN (8.5 mg) CDCl3) δ 174.4, 150.4, 147.4, 135.7, 129.8, 127.7, 125.8, 113.0,
and K2HPO4 (104.5 mg) and then evacuated and refilled with 52.2, 51.3, 48.7, 38.6, 34.6, 31.5, 30.4, 20.4. HRMS (ESI) m/z: [M
carbon dioxide (CO2) thrice following the usual Schlenk tech- + H]+ calcd for C23H32NO2 , 354.2428; found: 354.2428. IR (ν) =
+
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6301–6312 | 6305

View Article Online
Paper
Organic & Biomolecular Chemistry
2953, 2865, 1733, 1617, 1519, 1452, 1362, 1267, 1160, 1109,
Methyl 2-(3-methoxyphenyl)-4-(methyl(p-tolyl)amino)butano-
ate (3ha). The crude material was separated by silica gel
801, 747, 704 cm−1
.
Methyl 2-(4-isobutylphenyl)-4-(methyl(p-tolyl)amino)butano- column chromatography (10% ethyl acetate/n-hexane) to give
1
ate (3da). The crude material was separated by silica gel the desired product as a colorless oil (49.1 mg, 75%). H NMR
column chromatography (5% ethyl acetate/n-hexane) to give (400 MHz, CDCl3) δ 7.27 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.8 Hz,
1
the desired product as a colorless oil (42.4 mg, 60%). H NMR 2H), 6.92–6.83 (m, 3H), 6.62 (d, J = 8.6 Hz, 2H), 3.82, (s, 3H),
(400 MHz, CDCl3) δ 7.22 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 3.67 (s, 3H), 3.60 (t, J = 7.5 Hz, 3H), 3.33–3.20 (m, 2H), 2.88 (s,
2H), 7.03 (d, J = 8.5, 2H), 6.60 (d, J = 8.2 Hz, 2H), 3.67 (s, 3H), 3H), 2.43–2.34 (m, 1H), 2.27 (s, 3H), 2.07–2.03 (m, 1H). 13C
3.59 (t, J = 7.6 Hz, 1H), 3.30–3.23 (m, 2H), 2.87 (s, 3H), 2.48 (d, NMR (100 MHz, CDCl3) δ 174.1, 159.9, 147.3, 140.3, 129.8,
J = 7.2 Hz, 2H), 2.42–2.33 (m, 1H), 2.26 (s, 3H), 2.06–1.99 (m, 129.7, 125.8, 120.4, 113.6, 113.0, 55.3, 52.2, 51.1, 49.2, 38.6,
+
1H), 1.93–1.82 (m, 1H) 0.92 (d, J = 6.6 Hz, 6H). 13C NMR 30.2, 20.3. HRMS (ESI) m/z: [M + H]+ calcd for C20H26NO3 ,
(100 MHz, CDCl3) δ 174.4, 147.3, 140.0, 136.0, 129.8, 127.7, 328.1907; found: 328.1911. IR (ν) = 2949, 1731, 1677, 1599,
125.8, 113.0, 52.1, 51.2, 48.8, 45.2, 38.6, 30.3, 22.5, 20.3. HRMS 1519, 1487, 1452, 1347, 1259, 1161, 1117, 1043, 873, 802, 777,
(ESI) m/z: [M + H]+ calcd for C23H32NO2 , 354.2428; found: 695 cm−1
.
+
354.2428. IR (ν) = 2951, 2922, 2866, 1732, 1679, 1617, 1519,
1462, 1364, 1161, 1115, 959, 802, 746 cm−1
Methyl 4-(methyl(p-tolyl)amino)-2-(m-tolyl)butanoate (3ia).
The crude material was separated by silica gel column chrom-
.
Methyl 2-(4-methoxyphenyl)-4-(methyl(p-tolyl)amino)butanoate atography (5% ethyl acetate/n-hexane) to give the desired
1
(3ea). The crude material was separated by silica gel column product as a colorless oil (41.1 mg, 66%). H NMR (400 MHz,
chromatography (10% ethyl acetate/n-hexane) to give the CDCl3) δ 7.15 (t, J = 7.0 Hz, 1H), 7.02 (s, 1H), 7.00 (d, J = 7.1
desired product as a colorless oil (18.3 mg, 28%). 1H NMR Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 8.4 Hz, 2H), 3.56
(400 MHz, CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.4 Hz, (s, 3H), 3.47 (t, J = 7.8 Hz, 1H), 3.22–3.09 (m, 2H), 2.77 (s, 3H),
2H), 6.87 (d, J = 8.8, 2H), 6.59 (d, J = 8.1 Hz, 2H), 3.80 (s, 3H), 2.32–2.23 (m, 4H), 2.16 (s, 3H), 1.93–1.88 (m, 1H). 13C NMR
3.64 (s, 3H), 3.54 (t, J = 7.6 Hz, 1H), 3.26–3.20 (m, 2H), 2.86 (s, (100 MHz) δ 174.3, 147.3, 138.7, 138.5, 129.8, 128.7, 128.3,
3H), 2.37–2.32 (m, 1H), 2.25 (s, 3H), 2.03–1.96 (m, 1H). 13C 125.8, 125.1, 113.0, 52.2, 51.2, 49.1, 38.6, 30.2, 21.5, 20.3.
NMR (100 MHz, CDCl3)
δ
174.5, 159.0, 147.3, 130.8, HRMS (ESI) m/z: [M + H]+ calcd for C20H26NO2+, 312.1958;
129.8, 129.1, 125.8, 114.2, 113.0, 55.4, 52.2, 51.1, 48.3, found: 312.1961. IR (ν) = 2920, 2862, 1732, 1676, 1615, 1519,
38.63, 30.2, 20.3. HRMS (ESI) m/z: [M + H]+ calcd for 1455, 1164, 1116, 1043, 960, 882, 802, 698 cm−1
.
+
C20H26NO3 , 328.1907; found: 328.1909. IR (ν) = 2926, 1730,
Methyl
2-(2,5-dimethoxyphenyl)-4-(methyl(p-tolyl)amino)
1676, 1610, 1511, 1452, 1349, 1302, 1247, 1161, 1118, 1032, butanoate (3ja). The crude material was separated by silica gel
803, 734 cm−1
column chromatography (10% ethyl acetate/n-hexane) to give
.
1
Methyl 4-(methyl(p-tolyl)amino)-2-phenylbutanoate (3fa). the desired product as a colorless oil (48.6 mg, 68%). H NMR
The crude material was separated by silica gel column chrom- (400 MHz, CDCl3) δ 7.30 (d, J = 8.8 Hz, 2H), 6.84–6.77 (m, 3H),
atography (5% ethyl acetate/n-hexane) to give the desired 6.60 (d, J = 8.7 Hz, 2H), 4.04 (t, J = 7.4 Hz, 1H), 3.78 (s, 3H), 3.76
1
product as a colorless oil (49.4 mg, 83%). H NMR (400 MHz, (s, 3H), 3.67 (s, 3H), 3.34–3.20 (m, 2H), 2.87 (s, 3H), 2.36–2.27 (m,
CDCl3) δ 7.34–7.28 (m, 5H), 7.03 (d, J = 8.2 Hz, 2H), 6.59 (d, J = 1H), 2.25 (s, 3H), 1.99–1.94 (m, 1H). 13C NMR (100 MHz, CDCl3) δ
8.6, 2H), 3.66 (s, 3H), 3.61 (t, J = 7.3 Hz, 1H), 3.32–3.19 (m, 174.5, 153.8, 151.1, 147.4, 129.7, 128.7, 125.5, 114.5, 112.9, 112.8,
2H), 2.86 (s, 3H), 2.43–2.34 (m, 1H), 2.25 (s, 3H), 2.06–1.99 (m, 112.0, 56.3, 55.8, 52.1, 51.1, 42.0, 38.4, 29.2, 20.3. HRMS (ESI) m/
1H). 13C NMR (100 MHz, CDCl3) δ 174.2, 147.3, 138.8, 129.8, z: [M + H]+ calcd for C21H28ClNO4 , 358.2013; found: 358.2016. IR
+
128.8, 128.0, 127.5, 125.8, 113.0, 52.2, 51.1, 49.2, 38.6, 30.3, (ν) = 2946, 1731, 1615, 1499, 1461, 1351, 1223, 1174, 1117, 1046,
20.3. HRMS (ESI) m/z: [M + H]+ calcd for C19H24NO2 , 871, 802, 715 cm−1
.
+
298.1802; found: 298.1803. IR (ν) = 2862, 1732, 1677, 1616,
1519, 1452, 1351, 1209, 1160, 1043, 959, 802, 731, 700 cm−1
Methyl 4-(methyl(p-tolyl)amino)-2-(4-(trifluoromethyl)phenyl)
butanoate (3ka). The crude material was separated by silica gel
.
Methyl 2-(2-methoxyphenyl)-4-(methyl(p-tolyl)amino)butano- column chromatography (5% ethyl acetate/n-hexane) to give
1
ate (3ga). The crude material was separated by silica gel the desired product as a colorless oil (63.6 mg, 87%). H NMR
column chromatography (10% ethyl acetate/n-hexane) to give (400 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz,
1
the desired product as a colorless oil (43.9 mg, 67%). H NMR 2H), 7.04 (d, J = 8.2, 2H), 6.61 (d, J = 8.6 Hz, 2H), 3.71 (t, J = 8.2
(400 MHz, CDCl3) δ 7.18–7.13 (m, 2H), 6.92 (d, J = 8.7 Hz, 2H), Hz, 1H), 3.67 (s, 3H), 3.32–3.21 (m, 2H), 2.86 (s, 3H), 2.47–2.38
6.85 (td, J = 7.5, 1.1 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.49 (d, J = (m, 1H), 2.26 (s, 3H), 2.06–1.97 (m, 1H). 13C NMR (100 MHz,
8.5 Hz, 2H), 3.96, (t, J = 7.3 Hz, 1H), 3.73 (s, 3H), 3.56 (s, 3H), CDCl3) δ 173.5, 147.3, 142.8, 142.8, 129.9, 129.7, 128.5, 126.2,
3.25–3.10 (m, 2H), 2.76 (s, 3H), 2.77 (s, 3H), 2.27–2.18 (m, 1H), 125.9, 125.8, 125.8, 125.7, 125.5, 122.8, 113.1, 52.4, 51.1, 49.0,
2.15 (s, 3H), 1.90–1.86 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 38.7, 30.4, 20.3. 19F NMR (376 MHz, CDCl3) δ −62.4. HRMS
174.7, 156.8, 147.4, 129.7, 128.4, 127.7, 125.5, 120.9, 112.9, (ESI) m/z: [M + H]+ calcd for C20H23F3NO2+, 366.1675; found:
110.9, 55.6, 52.1, 51.1, 41.9, 38.4, 29.1, 20.3. HRMS (ESI) m/z: 366.1675. IR (ν) = 2928, 1733, 1617, 1435, 1419, 1323, 1161,
[M + H]+ calcd for C20H26NO3 , 328.1907; found: 328.1908. IR 1119, 1066, 1017, 958, 836, 802, 726 cm−1
.
+
(ν) = 2941, 2860, 1731, 1616, 1613, 1519, 1492, 1461, 1350,
Methyl 2-(4-cyanophenyl)-4-(methyl(p-tolyl)amino)butanoate
(3la). The crude material was separated by silica gel column
1243, 1158, 1118, 1027, 959, 801, 751 cm−1
.
6306 | Org. Biomol. Chem., 2021, 19, 6301–6312
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
chromatography (10% ethyl acetate/n-hexane) to give the (m, 1H), 7.04 (d, J = 8.2 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 3.66
desired product as a colorless oil (34.8 mg, 54%). 1H NMR (s, 3H), 3.57 (t, J = 8.0 Hz, 1H), 3.31–3.18 (m, 2H), 2.85 (s, 3H),
(400 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2.40–2.32 (m, 1H), 2.25 (s, 3H), 2.01–1.95 (m, 1H). 13C NMR
2H), 7.03 (d, J = 8.6, 2H), 6.57 (d, J = 8.6 Hz, 2H), 3.72–3.66 (m, (100 MHz, CDCl3) δ 173.6, 147.3, 140.7, 134.6, 130.1, 129.8,
4H), 3.30–3.19 (m, 2H), 2.84 (s, 3H), 2.45–2.36 (m, 1H), 2.25 (s, 128.3, 127.8, 126.3, 126.0, 113.1, 52.3, 51.1, 48.8, 38.7, 30.3,
+
3H), 2.03–1.94 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 173.1, 20.3. HRMS (ESI) m/z: [M + H]+ calcd for C19H23ClNO2 ,
147.2, 144.1, 132.6, 129.8, 129.0, 126.3, 118.7, 113.1, 111.5, 332.1412; found: 332.1413. IR (ν) = 2946, 2861, 1732, 1616,
52.5, 51.0, 49.2, 38.7, 30.4, 20.3. HRMS (ESI) m/z: [M + H]+ 1572, 1518, 1475, 1430, 1346, 1263, 1160, 1117, 1080, 1042,
calcd for C20H23N2O2 , 323.1754; found: 323.1753. IR (ν) = 960, 894, 801, 692 cm−1
.
+
2946, 2859, 2227, 1732, 1609, 1435, 1348, 1267, 1211, 1161,
958, 803, 704 cm−1
Methyl 2-(3-bromophenyl)-4-(methyl(p-tolyl)amino)butano-
ate (3qa). The crude material was separated by silica gel
.
Methyl 2-(4-bromophenyl)-4-(methyl(p-tolyl)amino)butano- column chromatography (5% ethyl acetate/n-hexane) to give
1
ate (3ma). The crude material was separated by silica gel the desired product as a colorless oil (68.5 mg, 91%). H NMR
column chromatography (5% ethyl acetate/n-hexane) to give (400 MHz, CDCl3) δ 7.46 (t, 1.6 Hz, 1H), 7.41 (dt, 7.5 Hz, 1.8
1
the desired product as a colorless oil (64.7 mg, 86%). H NMR Hz, 2H), 7.26–7.18 (m, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.59 (d, J =
(400 MHz, CDCl3) δ 7.46 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 8.6 Hz, 2H), 3.66 (s, 3H), 3.56 (t, J = 7.8 Hz, 1H), 3.29–3.18 (m,
2H), 7.03 (d, J = 8.2, 2H), 6.59 (d, J = 8.6 Hz, 2H), 3.65 (s, 3H), 2H), 2.86 (s, 3H), 2.41–2.32 (m, 1H), 2.26 (s, 3H), 2.02–1.93 h
3.57, (t, J = 7.6 Hz, 1H), 3.29–3.17 (m, 2H), 2.85 (s, 3H), (m, 1H). 13C NMR (100 MHz, CDCl3) δ 173.6, 147.2, 141.0,
2.41–2.32 (m, 1H), 2.26 (s, 3H), 2.00–1.95 (m, 1H). 13C NMR 131.2, 130.7, 130.4, 129.9, 126.8, 126.1, 122.9, 113.1, 52.4, 51.1,
(100 MHz, CDCl3) δ 173.8, 147.3, 137.8, 132.0, 129.8, 126.0, 48.8, 38.7, 30.3, 20.4. HRMS (ESI) m/z: [M + H]+ calcd for
+
121.5, 113.1, 52.3, 51.1, 48.6, 38.7, 30.2, 20.3. HRMS (ESI) m/z: C19H23BrNO2 , 376.0907; found: 376.0908. IR (ν) = 2944, 2860,
[M + H]+ calcd for C19H23BrNO2 , 376.0907; found: 376.0911. 1731, 1616, 1567, 1519, 1472, 1346, 1160, 1117, 1073, 996, 959,
+
IR (ν) = 2944, 2861, 1732, 1616, 1519, 1486, 1433, 1346, 1209, 886, 801 cm−1
.
1160, 1117, 1072, 1009, 959, 802, 756, 704 cm−1
.
Methyl 2-methyl-4-(methyl(p-tolyl)amino)-2-(4-(trifluoromethyl)
Methyl 2-(4-chlorophenyl)-4-(methyl(p-tolyl)amino)butano- phenyl)butanoate (3ra). The crude material was separated by
ate (3na). The crude material was separated by silica gel silica gel column chromatography (5% ethyl acetate/n-hexane)
column chromatography (5% ethyl acetate/n-hexane) to give to give the desired product as a pale yellow oil (48.6 mg, 64%).
1
the desired product as a colorless oil (59.7 mg, 90%). H NMR 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.44 (d, J
(400 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.4 Hz, = 8.2 Hz, 2H), 7.03 (d, J = 8.2, 2H), 6.55 (d, J = 8.2 Hz, 2H), 3.71
2H), 6.94 (d, J = 8.8, 2H), 6.50 (d, J = 8.7 Hz, 2H), 3.56 (s, 3H), (s, 3H), 3.29–3.20 (m, 2H), 2.85 (s, 3H), 2.34–2.26 (m, 1H), 2.25
3.50, (t, J = 7.5 Hz, 1H), 3.21–3.08 (m, 2H), 2.76 (s, 3H), (s, 3H), 2.16–2.08 (m, 1H), 1.66 (s, 3H). 13C NMR (100 MHz,
2.32–2.23 (m, 1H), 2.17 (s, 3H), 1.92–1.86 (m, 1H). 13C NMR CDCl3) δ 173.5, 147.3, 142.8, 142.8, 129.9, 129.7, 128.5, 126.2,
(100 MHz, CDCl3) δ 173.9, 147.3, 137.2, 133.4, 129.8, 129.4, 125.9, 125.8, 125.8, 125.7, 125.5, 122.8, 113.1, 52.4, 51.1, 49.0,
129.0, 126.0, 113.0, 52.3, 51.0, 48.1, 38.6, 30.3, 20.3. HRMS 38.7, 30.4, 20.3. 19F NMR (376 MHz, CDCl3) δ −62.4. HRMS
(ESI) m/z: [M + H]+ calcd for C19H23ClNO2 , 332.1412; found: (ESI) m/z: [M + H]+ calcd for C21H25F3NO2+, 380.1832; found:
+
332.1414. IR (ν) = 2923, 2860, 1732, 1616, 1519, 1490, 1451, 380.1833. IR (ν) = 2924, 1730, 1617, 1459, 1411, 1325, 1234,
1344, 1209, 1159, 1117, 1090, 1014, 959, 802, 747, 724 cm−1
.
1164, 1115, 1080, 1015, 952, 840, 802 cm−1
.
Methyl 2-(3,5-bis(trifluoromethyl)phenyl)-4-(methyl(p-tolyl)
Methyl 4-(methyl(p-tolyl)amino)-2,2-diphenylbutanoate (3sa).
amino)butanoate (3oa). The crude material was separated by The crude material was separated by silica gel column chrom-
silica gel column chromatography (5% ethyl acetate/n-hexane) atography (5% ethyl acetate/n-hexane) to give the desired
to give the desired product as a pale yellow solid (46.8 mg, product as a pale yellow oil (41.1 mg, 55%). 1H NMR
1
54%). H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.78 (s, 2H), (400 MHz, CDCl3) δ 7.38–7.29 (m, 10H), 7.01 (d, J = 8.5 Hz,
7.05 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 3.77 (t, J = 8.2 2H), 6.46 (d, J = 8.5, 2H), 3.77 (s, 3H), 3.16–3.12 (m, 2H), 2.86
Hz, 1H), 3.70 (s, 3H), 3.34–3.22 (m, 2H), 2.87 (s, 3H), 2.52–2.43 (s, 3H), 2.64–2.60 (m, 2H), 2.26 (s, 3H). 13C NMR (100 MHz,
(m, 1H), 2.27 (s, 3H), 2.09–2.00 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 174.5, 146.9, 142.9, 129.8, 128.8, 128.2, 127.1, 125.2,
CDCl3) δ172.9, 147.2, 141.3, 132.6, 132.3, 132.0, 131.6, 129.9, 112.3, 59.0, 52.6, 49.5, 38.2, 34.1, 20.3. HRMS (ESI) m/z: [M +
128.4, 127.4, 126.5, 124.7, 122.0, 121.7, 119.2, 113.3, 52.6, 51.0, H]+ calcd for C25H28NO2+, 374.2115; found: 374.2116. IR (ν) =
48.9, 38.7, 30.6, 20.3. 19F NMR (376 MHz, CDCl3) δ −62.7. 2944, 1726, 1616, 1519, 1444, 1364, 1312, 1223, 1189, 1118,
HRMS (ESI) m/z: [M + H]+ calcd for C21H22F6NO2 , 434.1549; 1063, 1030, 962, 801, 759, 697 cm−1
.
+
found: 434.1547. IR (ν) = 2952, 2867, 1724, 1617, 1519, 1370,
1274, 1166, 1126, 962, 905, 807, 682 cm−1
Methyl 4-(methyl(phenyl)amino)-2-phenylbutanoate (3fb).
The crude material was separated by silica gel column chrom-
.
Methyl 2-(3-chlorophenyl)-4-(methyl(p-tolyl)amino)butano- atography (5% ethyl acetate/n-hexane) to give the desired
1
ate (3pa). The crude material was separated by silica gel product as a colorless oil (32.3 mg, 57%). H NMR (400 MHz,
column chromatography (5% ethyl acetate/n-hexane) to give CDCl3) δ 7.36–7.20 (m, 7H), 6.72–6.65 (m, 3H), 3.65 (s, 3H),
1
the desired product as a colorless oil (57.1 mg, 86%). H NMR 3.61 (t, J = 7.6 Hz, 1H), 3.36–3.23 (m, 2H), 2.90 (s, 3H),
(400 MHz, CDCl3) δ 7.30 (s, 1H), 7.26–7.25 (m, 2H), 7.20–7.17 2.45–2.36 (m, 1H), 2.07–2.01 (m, 1H). 13C NMR (100 MHz,
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6301–6312 | 6307

View Article Online
Paper
Organic & Biomolecular Chemistry
CDCl3) δ 174.2, 149.2, 138.7, 129.3, 128.9, 128.0, 127.6, 116.5,
Methyl 4-((4-bromophenyl)(methyl)amino)-2-phenylbutano-
112.5, 52.2, 50.8, 49.2, 38.4, 30.4. HRMS (ESI) m/z: [M + H]+ ate (3fg). The crude material was separated by silica gel
+
calcd for C18H22NO2 , 284.1645; found: 284.1648. IR (ν) = 2951, column chromatography (5% ethyl acetate/n-hexane) to give
1
2834, 1735, 1616, 1512, 1436, 1322, 1242, 1161, 1118, 1066, the desired product as a colorless oil (44.2 mg, 61%). H NMR
1037, 1017, 945, 814, 710 cm−1
.
(400 MHz, CDCl3) δ 7.36–7.25 (m, 7H), 6.50 (d, J = 9.1 Hz, 2H),
Methyl 4-(methyl(m-tolyl)amino)-2-phenylbutanoate (3fc). 3.65 (s, 3H), 3.57 (t, J = 7.8 Hz, 1H), 3.33–3.19 (m, 2H), 2.86 (s,
The crude material was separated by silica gel column chrom- 3H), 2.42–2.33 (m, 1H), 2.03–1.98 (m, 1H). 13C NMR (100 MHz,
atography (5% ethyl acetate/n-hexane) to give the desired CDCl3) δ 174.1, 148.1, 138.6, 131.9, 128.9, 128.0, 127.7, 114.0,
1
product as a colorless oil (39.3 mg, 66%). H NMR (400 MHz, 108.3, 52.3, 50.7, 49.1, 38.5, 30.2. HRMS (ESI) m/z: [M + H]+
+
CDCl3) δ 7.39–7.31 (m, 5H), 7.13 (t, J = 7.9 Hz, 1H), 6.56–6.47 calcd for C18H21BrNO2 , 362.0750; found: 362.0755. IR (ν) =
(m, 3H), 3.68 (s, 3H), 3.63 (t, J = 7.7 Hz, 1H), 3.32–3.25 (m, 2H), 2926, 1726, 1584, 1493, 1378, 1348, 1212, 1163, 1119, 1007,
2.90 (s, 3H), 2.46–2.31 (m, 1H), 2.32 (s, 3H), 2.11–2.04 (m, 1H). 964, 877, 807, 735, 701 cm−1
.
13C NMR (100 MHz, CDCl3) δ 174.2, 149.3, 138.9, 138.7, 129.1,
Methyl 4-((4-fluorophenyl)(methyl)amino)-2-phenylbutano-
128.9, 128.1, 127.6, 120.1, 117.4, 113.3, 109.7, 52.2, 50.8, 49.1, ate (3fh). The crude material was separated by silica gel
38.4, 30.3, 22.0. HRMS (ESI) m/z: [M
+
H]+ calcd for column chromatography (5% ethyl acetate/n-hexane) to give
+
1
C19H24NO2 , 298.1802; found: 298.1804. IR (ν) = 3028, 2948, the desired product as a colorless oil (10.8 mg, 18%). H NMR
1731, 1600, 1496, 1452, 1352, 1226, 1159, 1119, 1027, 836, 765, (400 MHz, CDCl3) δ 7.36–7.26 (m, 5H), 6.94–6.89 (m, 2H),
732, 694 cm−1
.
6.60–6.56 (m, 2H), 3.65 (s, 3H), 3.59 (t, J = 7.2 Hz, 1H),
Methyl 4-((3,5-dimethylphenyl)(methyl)amino)-2-phenylbu- 3.30–3.16 (m, 2H), 2.85 (s, 3H), 2.42–2.33 (m, 1H), 2.03–1.99
tanoate (3fd). The crude material was separated by silica gel (m, 1H). 13C NMR (100 MHz, CDCl3) δ 174.2, 156.7, 154.3,
column chromatography (5% ethyl acetate/n-hexane) to give 146.1, 138.7, 128.9, 128.0, 127.6, 115.7, 115.5, 113.9, 113.8,
1
the desired product as a colorless oil (34.3 mg, 51%). H NMR 52.2, 51.5, 49.1, 38.9, 30.2. 19F NMR (376 MHz, CDCl3) δ
+
(400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 6.38 (s, 1H), 6.27 (s, −129.1. HRMS (ESI) m/z: [M + H]+ calcd for C18H21FNO2 ,
2H), 3.67 (s, 3H), 3.61 (t, J = 7.6 Hz, 1H), 3.26 (t, J = 7.6 Hz, 302.1551; found: 302.1553. IR (ν) = 2949, 1730, 1602, 1509,
2H), 2.88 (s, 3H), 2.43–2.34 (m, 1H), 2.26 (s, 6H), 2.10–2.01 (m, 1351, 1267, 1225, 1159, 1118, 1044, 958, 813, 732, 697 cm−1
.
1H). 13C NMR (100 MHz, CDCl3) δ 174.2, 149.4, 138.8, 138.7,
Methyl 4-(diphenylamino)-2-phenylbutanoate (3fi). The
128.9, 128.1, 127.6, 118.6, 110.5, 52.2, 50.7, 49.1, 38.4, 30.3, crude material was separated by silica gel column chromato-
+
21.9. HRMS (ESI) m/z: [M + H]+ calcd for C20H26NO2 , graphy (5% ethyl acetate/n-hexane) to give the desired
312.1958; found: 312.1961. IR (ν) = 2945, 2917, 1731, 1597, product as
a
colorless oil (58.7 mg, 85%). 1H NMR
1487, 1452, 1363, 1265, 1204, 1160, 1124, 1032, 988, 909, 917, (400 MHz, CDCl3) δ 7.25–7.14 (m, 10H), 6.68–6.84 (m, 5H),
731, 670 cm−1
.
3.64–3.43 (m, 6H), 2.45–2.35 (m, 1H), 2.09–2.00 (m, 1H). 13C
Methyl
4-((4-methoxyphenyl)(methyl)amino)-2-phenylbu- NMR (100 MHz, CDCl3) δ 174.1, 147.9, 138.6, 129.4, 128.9,
tanoate (3fe). The crude material was separated by silica gel 128.0, 127.6, 121.5, 121.1, 52.3, 50.3, 49.2, 31.2. HRMS (ESI) m/
column chromatography (10% ethyl acetate/n-hexane) to give z: [M + H]+ calcd for C23H24NO2+, 346.1802; found: 346.1799.
1
the desired product as a colorless oil (23.2 mg, 37%). H NMR IR (ν) = 2947, 1732, 1588, 1494, 1454, 1362, 1218, 1161, 1070,
(400 MHz, CDCl3) δ 7.35–7.26 (m, 5H), 6.81 (d, J = 9.0 Hz, 3H), 748, 697 cm−1
.
6.65 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H), 3.65 (s, 3H), 3.61 (t, J = 7.6
Methyl 4-(9H-carbazol-9-yl)-2-phenylbutanoate (3fj). The
Hz, 1H), 3.25–3.14 (m, 2H), 2.82 (s, 3H), 2.41–2.32 (m, 1H), crude material was separated by silica gel column chromato-
2.03–1.95 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 174.3, 151.9, graphy (5% ethyl acetate/n-hexane) to give the desired product
144.4, 138.9, 128.9, 128.1, 127.5, 114.9, 114.8, 55.9, 52.2, 52.0, as a colorless powder (60.4 mg, 88%). 1H NMR (400 MHz,
49.2, 39.1, 30.3. HRMS (ESI) m/z: [M + H]+ calcd for C19H24NO3 , CDCl3) δ 8.14 (d, J = 8.2 Hz, 2H), 7.49 (td, J = 8.2, 1.2 Hz, 5H),
+
314.1751; found: 314.1753. IR (ν) = 2948, 1730, 1601, 1511, 1452, 7.40–7.25 (m, 9H), 4.33 (t, J = 7.4 Hz, 2H), 3.68 (s, 3H), 3.63 (t, J
1351, 1242, 1160, 1118, 1036, 958, 814, 732, 698 cm−1
.
= 7.4 Hz, 1H), 2.77–2.68 (m, 1H), 2.41–2.32 (m, 1H). 13C NMR
Methyl 4-((4-chlorophenyl)(methyl)amino)-2-phenylbutano- (100 MHz, CDCl3) δ 173.8, 140.3, 138.2, 129.0, 128.0, 127.8,
ate (3ff). The crude material was separated by silica gel 125.8, 123.0, 120.5, 119.1, 108.7, 52.3, 48.7, 40.9, 32.0. HRMS
column chromatography (5% ethyl acetate/n-hexane) to give (ESI) m/z: [M + H]+ calcd for C23H22NO2 , 344.1645; found:
+
1
the desired product as a colorless oil (45.8 mg, 72%). H NMR 344.1644. IR (ν) = 3054, 2950, 1723, 1594, 1485, 1452, 1326,
(400 MHz, CDCl3) δ 7.37–7.29 (m, 5H), 7.14 (d, J = 9.1 Hz, 2H), 1212, 1160, 1122, 1055, 1028, 969, 749, 724, 698 cm−1
.
6.55 (d, J = 9.0 Hz, 2H), 3.65 (s, 3H), 3.57 (t, J = 7.4 Hz, 1H),
Methyl 4-(9H-carbazol-9-yl)-2-phenylbutanoate (3fk). The
3.34–3.19 (m, 2H), 2.87 (s, 3H), 2.42–2.33 (m, 1H), 2.04–1.99 crude material was separated by silica gel column chromato-
(m, 1H). 13C NMR (100 MHz, CDCl3) δ 174.0, 147.7, 138.6, graphy (5% ethyl acetate/n-hexane) to give the desired product
1
129.0, 128.9, 128.0, 127.7, 121.2, 113.5, 52.3, 50.9, 49.1, 38.5, as a colorless oil (44.6 mg, 72%). H NMR (400 MHz, CDCl3) δ
30.2. HRMS (ESI) m/z: [M + H]+ calcd for C18H21ClNO2 , 7.66–7.63 (m, 1H), 7.47–7.44 (m, 1H), 7.31 (d, J = 4.4 Hz, 4H),
+
318.1255; found: 318.1259. IR (ν) = 2948, 1730, 1595, 1498, 7.27–7.17 (m, 8H), 7.02 (t, J = 7.3 Hz, 2H), 6.65 (d, J = 7.9 Hz,
1453, 1352, 1189, 1161, 1118, 1044, 958, 909, 808, 731, 1H), 6.61 (t, J = 7.3 Hz), 6.52 (t, J = 7.3 Hz), 6.18 (d, J = 7.9 Hz),
698 cm−1
.
4.42 (q, J = 6.4 Hz), 3.65 (s, 3H), 3.59–3.48 (m 5H), 3.44–3.36
6308 | Org. Biomol. Chem., 2021, 19, 6301–6312
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
1
(m, 1H), 3.36–3.30 (m, 2H), 3.11–3.00 (m, 2H), 2.65–2.59 (m, (63.3 mg, 83%). H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.4
1H), 2.20–2.13 (m, 1H), 2.02–1.72 (m 10 H). 13C NMR Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.87–6.79 (m, 2H), 6.69–6.64
(100 MHz, CDCl3) δ 174.2, 147.3, 147.1, 139.4, 138.5, 131.1, (m, 2H), 3.76 (s, 3H), 3.70 (t, J = 7.3 Hz, 1H), 3.66 (s, 3H),
129.4, 129.1, 129.0, 128.9, 128.5, 127.8, 127.8, 127.5, 115.8, 3.27–3.13 (m, 2H), 2.82 (s, 3H), 2.45–2.36 (m, 1H), 2.04–1.95
115.6, 112.1, 112.1, 57.1, 55.9, 52.9, 52.2, 49.4, 49.3, 48.3, 36.9, (m, 1H). 13C NMR (100 MHz, CDCl3) δ 173.5, 152.1, 144.3,
36.3, 30.2, 30.1, 29.9, 23.5, 23.4. HRMS (ESI) m/z: [M + H]+ 142.9, 130.0, 129.7, 128.5, 125.8, 125.8, 125.5, 122.8, 115.9,
+
calcd for C20H24NO2 , 310.1802; found: 310.1800. IR (ν) = 2925, 114.8, 55.8, 52.4, 51.9, 49.0, 39.3, 30.4. 19F NMR (376 MHz,
2854, 1731, 1598, 1503, 1454, 1363, 1267, 1197, 1156, 1071, CDCl3)
1032, 908, 729, 694 cm−1 C19H21F3NO2+, 382.1625; found: 382.1627. IR (ν) = 2951, 1734,
Methyl 4-(methyl(phenyl)amino)-2-(4-(trifluoromethyl)phenyl) 1601, 1497, 1323, 1161, 1120, 1067, 1017, 836, 766, 692 cm−1
butanoate (3kb). The crude material was separated by silica gel Methyl 4-((4-chlorophenyl)(methyl)amino)-2-(4-(trifluoro-
δ −62.4. HRMS (ESI) m/z: [M +
H]+ calcd for
.
.
column chromatography (5% ethyl acetate/n-hexane) to give methyl)phenyl)butanoate (3kf). The crude material was sep-
1
the desired product as a colorless oil (59.7 mg, 85%). H NMR arated by silica gel column chromatography (5% ethyl acetate/
(400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, n-hexane) to give the desired product as a colorless oil
1
2H), 7.26–7.22 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 8.1 (59.4 mg, 77%). H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.1
Hz, 2H), 3.71 (t, J = 7.2 Hz, 1H), 3.67 (s, 3H), 3.39–3.25 (m, 2H), Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.56
2.91 (s, 3H), 2.50–2.40 (m, 1H), 2.07–2.02 (m, 1H). 13C NMR (d, J = 8.9 Hz 2H), 3.67 (s, 3H), 3.65 (t, J = 8.3 Hz, 1H),
(100 MHz, CDCl3) δ 173.5, 149.2, 142.7, 130.0, 129.7, 129.3, 3.36–3.20 (m, 2H), 2.87 (s, 3H), 2.45–2.36 (m, 1H), 2.03–1.95
128.5, 125.8, 125.8, 125.5, 122.8, 116.7, 112.6, 52.4, 50.7, 49.0, (m, 1H). 13C NMR (100 MHz, CDCl3) δ 173.3, 147.8, 142.6,
38.4, 30.4. 19F NMR (376 MHz, CDCl3) δ −62.4. HRMS (ESI) m/ 130.1, 129.8, 129.1, 128.4, 125.9, 125.8, 125.5, 122.8, 121.5,
z: [M + H]+ calcd for C19H21F3NO2+, 352.1519; found: 352.1518. 113.6, 52.5, 50.8, 49.0, 38.6, 30.3. 19F NMR (376 MHz, CDCl3) δ
IR (ν) = 2956, 1734, 1599, 1505, 1323, 1162, 1119, 1075, 1018, −62.5. HRMS (ESI) m/z: [M + H]+ calcd for C19H20ClF3NO2 ,
+
837, 748, 692 cm−1
.
386.1129; found: 386.1131. IR (ν) = 2951, 1733, 1619, 1595,
Methyl 4-(methyl(m-tolyl)amino)-2-(4-(trifluoromethyl)phenyl) 1499, 1435, 1323, 1161, 1119, 1066, 1017, 956, 808 cm−1
butanoate (3kc). The crude material was separated by silica gel Methyl 4-((4-bromophenyl)(methyl)amino)-2-(4-(trifluoro-
.
column chromatography (5% ethyl acetate/n-hexane) to give methyl)phenyl)butanoate (3kg). The crude material was sep-
1
the desired product as a colorless oil (59.9 mg, 82%). H NMR arated by silica gel column chromatography (5% ethyl acetate/
(400 MHz, CDCl3) δ 7.61 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, n-hexane) to give the desired product as a colorless oil
1
2H), 7.12 (dd, J = 8.0, 7.6 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 6.48 (63.7 mg, 74%). H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.2
(dd, J = 8.2 Hz, 1H), 6.44 (s, 1H), 3.71–3.65 (m, 4H), 3.34–3.22 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 9.1 Hz, 2H), 6.56
(m, 2H), 2.89 (s, 3H), 2.48–2.39 (m, 1H), 2.30(s, 1H), 2.09–2.00 (d, J = 9.1 Hz 2H), 3.72 (s, 3H), 3.70 (t, J = 6.9 Hz, 1H),
(m, 1H). 13C NMR (100 MHz, CDCl3) δ 173.5, 149.3, 142.7, 3.41–3.25 (m, 2H), 2.92 (s, 3H), 2.51–2.42 (m, 1H), 2.08–2.03
139.0, 130.0, 129.7, 129.2, 128.5, 125.8, 125.8, 125.7, 125.5, (m, 1H). 13C NMR (100 MHz, CDCl3) δ 173.3, 148.1, 142.6,
122.8, 117.7, 115.4, 113.4, 109.8, 52.4, 50.7, 49.0, 38.4, 30.4, 132.0, 130.1, 129.8, 128.4, 125.9, 125.9, 125.5, 122.8, 114.1,
22.0. 19F NMR (376 MHz, CDCl3) δ −62.4. HRMS (ESI) m/z: [M 108.6, 52.5, 50.7, 48.9, 38.5, 30.3. 19F NMR (376 MHz, CDCl3) δ
+
+
+ H]+ calcd for C20H23F3NO2 , 366.1675; found: 366.1674. IR −62.4. HRMS (ESI) m/z: [M + H]+ calcd for C19H20BrF3NO2 ,
(ν) = 2951, 1734, 1601, 1497, 1435, 1323, 1160, 1119, 1066, 430.0624; found: 430.0625. IR (ν) = 2951, 1732, 1617, 1590,
1017, 835, 765, 692 cm−1
.
1497, 1434, 1369, 1323, 1161, 1118, 1067, 1017, 836, 806,
Methyl 4-((3,5-dimethylphenyl)(methyl)amino)-2-(4-(trifluor- 724 cm−1
omethyl)phenyl)butanoate (3kd). The crude material was sep- Methyl 4-((4-fluorophenyl)(methyl)amino)-2-(4-(trifluoromethyl)
.
arated by silica gel column chromatography (5% ethyl acetate/ phenyl)butanoate (3kh). The crude material was separated by
n-hexane) to give the desired product as a colorless oil silica gel column chromatography (5% ethyl acetate/n-hexane) to
1
(65.3 mg, 86%). H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.2 give the desired product as a colorless oil (51.7 mg, 70%). 1H
Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 6.40 (s, 1H), 6.27 (s, 2H), NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2
3.71–3.67 (m, 4H), 3.33–3.21 (m, 2H), 2.88 (s, 3H), 2.47–2.38 Hz, 2H), 6.93–6.89 (m, 2H), 6.60–6.56 (m, 2H), 3.68–3.64 (m, 4H),
(m, 1H), 2.27(s, 1H), 2.10–2.02 (m, 1H). 13C NMR (100 MHz, 3.31–3.16 (m, 2H), 2.83 (s, 3H), 2.44–2.35 (m, 1H), 2.01–1.95 (m,
CDCl3) δ 173.5, 149.4, 142.8, 138.8, 130.0, 129.7, 128.6, 125.8, 1H). 13C NMR (100 MHz, CDCl3) δ 173.5, 149.2, 142.7, 130.0,
125.8, 118.8, 110.6, 52.4, 50.6, 48.9, 38.4, 30.4, 21.9. 19F NMR 129.7, 129.3, 128.5, 125.8, 125.8, 125.5, 122.8, 116.7, 112.6, 52.4,
(376 MHz, CDCl3) δ −62.4. HRMS (ESI) m/z: [M + H]+ calcd for 50.7, 49.0, 38.4, 30.4. 19F NMR (376 MHz, CDCl3) δ −62.4, −128.7.
C21H25F3NO2+, 380.1832; found: 380.1830. IR (ν) = 2952, 1734, HRMS (ESI) m/z: [M + H]+ calcd for C19H20F4NO2 , 370.1425;
+
1597, 1487, 1436, 1323, 1162, 1121, 1067, 1018, 989, 818, found: 370.1425. IR (ν) = 2952, 1733, 1618, 1510, 1435, 1324,
691 cm−1
.
1227, 1067, 1119, 1161, 1018, 957, 813, 699 cm−1
.
Methyl 4-((4-methoxyphenyl)(methyl)amino)-2-(4-(trifluoro-
methyl)phenyl)butanoate (3ke). The crude material was separ-
Procedure for the gram scale reaction
ated by silica gel column chromatography (10% ethyl acetate/ A 250 mL Schleck tube was charged with 4CzBnBN (170 mg)
n-hexane) to give the desired product as a colorless oil and K2HPO4 (2.09 g) and then evacuated and refilled with
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6301–6312 | 6309

View Article Online
Paper
Organic & Biomolecular Chemistry
carbon dioxide (CO2) thrice following the usual Schlenk tech- and editing: H. Hahm and S. Hong; funding acquisition: S.
nique. DMF (40 mL), 1k (591 μL, 4 mmol) and 2e (1.81 g, Hong.
12 mmol) were added under a flow of CO2 and the Schlenk
tube was closed. Then, the reaction was conducted in the
Schlenk tube irradiated with Kessil LED light (A80, Tuna Blue, Conflicts of interest
15 W; the distance between the Schlenk tube and the LED was
There are no conflicts to declare.
about 6–8 cm) for 12 h at room temperature (28–32 °C). The
reaction was cooled using a fan. After the completion of the
reaction, it was quenched with 1 M HCl (40 mL) and extracted
with ethyl acetate (100 mL ×3). The combined organic phase
Acknowledgements
was dried using MgSO4 and filtered, and ethyl acetate was
This research was supported by the National Research
evaporated. The crude product was dissolved in diethyl ether
Foundation of Korea (NRF) grant funded by the Korean govern-
(160 mL) and MeOH (40 mL) at 0 °C. Then, trimethyl-
ment (Ministry of Science and ICT) (NRF-2020R1A2C1009123).
silyldiazomethane (2 M in ether, 4 mL) was added dropwise to
the mixture. The resulting mixture was stirred at room temp-
erature for 1 h. The solvent in the crude material was evapor-
ated and the crude material was separated by silica gel column
Notes and references
chromatography (5% ethyl acetate/n-hexane).
1 L. J. Goossen, N. Rodriguez and K. Goossen, Angew. Chem.,
Int. Ed., 2008, 47, 3100–3120.
Procedure for the synthesis of lactam17
2 (a) H. Arakawa, M. Aresta, J. N. Armor, M. A. Barteau,
E. J. Beckman, A. T. Bell, J. E. Bercaw, C. Creutz, E. Dinjus,
D. A. Dixon, K. Domen, D. L. DuBois, J. Eckert, E. Fujita,
D. H. Gibson, W. A. Goddard, D. W. Goodman, J. Keller,
G. J. Kubas, H. H. Kung, J. E. Lyons, L. E. Manzer,
T. J. Marks, K. Morokuma, K. M. Nicholas, R. Periana,
L. Que, J. Rostrup-Nielson, W. M. H. Sachtler,
L. D. Schmidt, A. Sen, G. A. Somorjai, P. C. Stair,
B. R. Stults and W. Tumas, Chem. Rev., 2001, 101, 953–996;
(b) A. M. Appel, J. E. Bercaw, A. B. Bocarsly, H. Dobbek,
D. L. DuBois, M. Dupuis, J. G. Ferry, E. Fujita, R. Hille,
P. J. Kenis, C. A. Kerfeld, R. H. Morris, C. H. Peden,
A. R. Portis, S. W. Ragsdale, T. B. Rauchfuss, J. N. Reek,
L. C. Seefeldt, R. K. Thauer and G. L. Waldrop, Chem. Rev.,
2013, 113, 6621–6658.
3 (a) T. Sakakura, J.-C. Choi and H. Yasuda, Chem. Rev., 2007,
107, 2365–2387; (b) M. Cokoja, C. Bruckmeier, B. Rieger,
W. A. Herrmann and F. E. Kuhn, Angew. Chem., Int. Ed.,
2011, 50, 8510–8537; (c) I. Omae, Coord. Chem. Rev., 2012,
256, 1384–1405; (d) Y. Tsuji and T. Fujihara, Chem.
Commun., 2012, 48, 9956–9964; (e) M. Aresta,
A. Dibenedetto and A. Angelini, Chem. Rev., 2014, 114,
1709–1742; (f) C. S. Yeung and V. M. Dong, Top. Catal.,
2014, 57, 1342–1350; (g) Q. Liu, L. Wu, R. Jackstell and
M. Beller, Nat. Commun., 2015, 6, 5933; (h) L. Song,
Y.-X. Jiang, Z. Zhang, Y.-Y. Gui, X.-Y. Zhou and D.-G. Yu,
Chem. Commun., 2020, 56, 8355–8367; (i) C.-K. Ran,
X.-W. Chen, Y.-Y. Gui, J. Liu, L. Song, K. Ren and D.-G. Yu,
Sci. China: Chem., 2020, 1–16.
To a 10 mL vial under an argon atmosphere were added
sequentially 3ke (38.1 mg, 0.1 mmol, 1 equiv.), MeCN (1 mL),
water (1 mL), periodic acid (22.8 mg, 0.1 mmol, 1 equiv.), and
1.0 M aqueous H2SO4 (0.1 mL). The reaction mixture was
stirred for 24 h at room temperature, and then diluted with
water (10 mL) and washed with dichloromethane (3 × 10 mL).
The aqueous layer was evaporated in vacuo. To the resultant
mixture were added trimethylamine (27.9 μL, 0.2 mmol, 2
equiv.) and toluene (2 mL). The resultant mixture was placed
in a heating bath and heated to reflux for 24 h, and then
cooled to room temperature. The mixture was filtered and
toluene was evaporated. The solid mixture was separated by
silica gel column chromatography (ethyl acetate/n-hexane =
1 : 1) and the desired lactam product 5 was obtained as a color-
less powder.
1-Methyl-3-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one (5).
The crude material was separated by silica gel column chrom-
atography (50% ethyl acetate/n-hexane) to give the desired
product as a colorless powder (18 mg, 74%). 1H NMR
(400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.8 Hz,
2H), 3.72 (t, 9.0 Hz, 1H), 3.49–3.44 (m, 2H), 2.94 (s, 3H),
2.58–2.52 (m, 1H), 2.17–2.07 (m, 1H). 13C NMR (100 MHz,
CDCl3) δ 174.1, 144.0, 129.5, 129.2, 128.5, 125.8, 125.8, 125.7,
125.7, 122.9, 47.9, 47.7, 30.3, 27.9. 19F NMR (376 MHz, CDCl3)
δ −62.4. HRMS (ESI) m/z: [M + H]+ calcd for C12H13F3NO+,
244.0944; found: 244.0945. IR (ν) = 2928, 2856, 1673, 1617,
1493, 1421, 1327, 1288, 1255, 1155, 1107, 1068, 1015, 844, 781,
713 cm−1
.
4 (a) T. Leon, A. Correa and R. Martin, J. Am. Chem. Soc.,
2013, 135, 1221–1224; (b) A. Correa, T. Leon and R. Martin,
J. Am. Chem. Soc., 2014, 136, 1062–1069; (c) S. Zhang,
W.-Q. Chen, A. Yu and L.-N. He, ChemCatChem, 2015, 7,
3972–3977; (d) M. Borjesson, T. Moragas, D. Gallego and
R. Martin, ACS Catal., 2016, 6, 6739–6749; (e) T. Moragas,
M. Gaydou and R. Martin, Angew. Chem., Int. Ed., 2016, 55,
5053–5057.
Author contributions
Conceptualization: H. Hahm and S. Hong; methodology:
H. Hahm and S. Hong; investigation: H. Hahm, J. Kim,
J. Y. Ryoo, and M. S. Han; data curation: H. Hahm, J. Kim, and
J. Y. Ryoo; writing – original draft: H. Hahm; writing – review
6310 | Org. Biomol. Chem., 2021, 19, 6301–6312
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
5 (a) C. M. Williams and T. Rovis, J. Am. Chem. Soc., 2008,
130, 14936–14937; (b) M. D. Greenhalgh and S. P. Thomas,
L. L. Liao and D. G. Yu, Nat. Commun., 2019, 10, 3592;
(f) H. Wang, Y. Gao, C. Zhou and G. Li, J. Am. Chem. Soc.,
2020, 142, 8122–8129; (g) B. Zhang, Y. Yi, Z.-Q. Wu,
C. Chen and C. Xi, Green Chem., 2020, 22, 5961–5965;
(h) W. J. Zhou, Z. H. Wang, L. L. Liao, Y. X. Jiang, K. G. Cao,
T. Ju, Y. Li, G. M. Cao and D. G. Yu, Nat. Commun., 2020,
11, 3263; (i) L. L. Liao, G. M. Cao, Y. X. Jiang, X. H. Jin,
X. L. Hu, J. J. Chruma, G. Q. Sun, Y. Y. Gui and D. G. Yu,
J. Am. Chem. Soc., 2021, 143, 2812–2821; ( j) C. Zhou, M. Li,
J. Sun, J. Cheng and S. Sun, Org. Lett., 2021, 23, 2895–2899;
(k) L. Song, D. M. Fu, L. Chen, Y. X. Jiang, J. H. Ye, L. Zhu,
Y. Lan, Q. Fu and D.-G. Yu, Angew. Chem., 2020, 132,
21307–21314; (l) H. Hahm, D. Beak, D. Kim, S. Park,
J. Y. Ryoo and S. Hong, Org. Lett., 2021, 23, 3879–3884;
(m) J.-H. Ye, T. Ju, H. Huang, L.-L. Liao and D.-G. Yu, Acc.
Chem. Res., 2021, 54, 2518–2531; (n) T. Ju, Y.-Q. Zhou,
K.-G. Cao, Q. Fu, J.-H. Ye, G.-Q. Sun, X.-F. Liu, L. Chen,
L.-L. Liao and D.-G. Yu, Nat. Catal., 2021, 4, 304–311.
8 (a) A. J. McCarroll and J. C. Walton, Angew. Chem., Int. Ed.,
2001, 40, 2224–2248; (b) E. Merino and C. Nevado, Chem.
Soc. Rev., 2014, 43, 6598–6608; (c) T. Koike and M. Akita,
Org. Chem. Front., 2016, 3, 1345–1349; (d) G. Yin, X. Mu
and G. Liu, Acc. Chem. Res., 2016, 49, 2413–2423;
(e) X.-W. Lan, N.-X. Wang and Y. Xing, Eur. J. Org. Chem.,
2017, 5821–5851; (f) J. S. Zhang, L. Liu, T. Chen and
L. B. Han, Chem. – Asian J., 2018, 13, 2277–2291.
9 (a) B. A. Sachais, J. N. Logue and M. S. Carey, Arch. Neurol.,
1977, 34, 422–428; (b) G. H. Fromm, C. F. Terrence,
A. S. Chattha and J. D. Glass, Arch. Neurol., 1980, 37, 768–
771; (c) D. H. Rich, J. Med. Chem., 1985, 28, 263–273;
(d) K. Stratmann, D. L. Burgoyne, R. E. Moore and
G. M. L. Patterson, J. Org. Chem., 1994, 59, 7219–7226;
(e) P. Yuen, G. D. Kanter, C. P. Taylor and M. G. Vartanian,
Bioorg. Med. Chem. Lett., 1994, 4, 823–826; (f) J. Zhu, E. Mix
and B. Winblad, CNS Drug Rev., 2001, 7, 387–398;
(g) I. Lapin, CNS Drug Rev., 2001, 7, 471–481;
(h) R. B. Silverman, Angew. Chem., Int. Ed., 2008, 47, 3500–
3504; (i) R. H. Prager and K. Schafer, Aust. J. Chem., 1997,
50, 813–824.
J.
Am.
Chem.
Soc.,
2012,
134,
11900–11903;
(c) S. Kawashima, K. Aikawa and K. Mikami, Eur. J. Org.
Chem., 2016, 3166–3170; (d) P. Shao, S. Wang, C. Chen and
C. Xi, Org. Lett., 2016, 18, 2050–2053.
6 (a) Y. Cao, X. He, N. Wang, H.-R. Li and L.-N. He,
Chin. J. Chem., 2018, 36, 644–659; (b) J. Hou, J.-S. Li and
J. Wu, Asian J. Org. Chem., 2018, 7, 1439–1447; (c) Y. Yang
and J. W. Lee, Chem. Sci., 2019, 10, 3905–3926;
(d) C. S. Yeung, Angew. Chem., 2019, 58, 5492–5502;
(e) X. He, L.-Q. Qiu, W.-J. Wang, K.-H. Chen and L.-N. He,
Green Chem., 2020, 22, 7301–7320; (f) Q. Y. Meng, S. Wang
and B. Konig, Angew. Chem., Int. Ed., 2017, 56, 13426–
13430; (g) K. Murata, N. Numasawa, K. Shimomaki,
J. Takaya and N. Iwasawa, Chem. Commun., 2017, 53, 3098–
3101; (h) H. Seo, M. H. Katcher and T. F. Jamison, Nat.
Chem., 2017, 9, 453–456; (i) H. Seo, A. Liu and
T. F. Jamison, J. Am. Chem. Soc., 2017, 139, 13969–13972;
( j) K. Shimomaki, K. Murata, R. Martin and N. Iwasawa,
J. Am. Chem. Soc., 2017, 139, 9467–9470; (k) L. L. Liao,
G. M. Cao, J. H. Ye, G. Q. Sun, W. J. Zhou, Y. Y. Gui,
S. S. Yan, G. Shen and D. G. Yu, J. Am. Chem. Soc., 2018,
140, 17338–17342; (l) Q. Y. Meng, S. Wang, G. S. Huff and
B. Konig, J. Am. Chem. Soc., 2018, 140, 3198–3201;
(m) B. Sahoo, P. Bellotti, F. Julia-Hernandez, Q. Y. Meng,
S. Crespi and B. Konig, R. Martin, Chemistry, 2019, 25,
9001–9005; (n) K. Shimomaki, T. Nakajima, J. Caner,
N. Toriumi and N. Iwasawa, Org. Lett., 2019, 21, 4486–4489;
(o) C. Zhu, Y. F. Zhang, Z. Y. Liu, L. Zhou, H. Liu and
C. Feng, Chem. Sci., 2019, 10, 6721–6726; (p) T. Ju, Q. Fu,
J. H. Ye, Z. Zhang, L. L. Liao, S. S. Yan, X. Y. Tian, S. P. Luo,
J. Li and D.-G. Yu, Angew. Chem., Int. Ed., 2018, 57, 13897–
13901; (q) Y. Chen, L.-Q. Lu, D.-G. Yu, C.-J. Zhu and
W.-J. Xiao, Sci. China: Chem., 2019, 62, 24–57; (r) Z. Zhen,
G. Li, Z. Xiao-Yu, Y. Si-Shun, L. Jing and D.-G. Yu, Acta
Chim. Sin., 2019, 77, 783–793; (s) Z. Fan, Z. Zhang and
C. Xi, ChemSusChem, 2020, 13, 6201–6218; (t) H. Huang,
J.-H. Ye, L. Zhu, C.-K. Ran, M. Miao, W. Wang, H. Chen,
W.-J. Zhou, Y. Lan, B. Yu and D.-G. Yu, CCS Chem., 2020, 10 (a) L. Guo, Y. Chi, A. M. Almeida, I. A. Guzei, B. K. Parker
1746–1756; (u) Y. X. Jiang, L. Chen, C. K. Ran, L. Song,
W. Zhang, L. L. Liao and D.-G. Yu, ChemSusChem, 2020, 13,
6312–6317; (v) B. Cai, H. W. Cheo, T. Liu and J. Wu,
Angew. Chem., Int. Ed., 2021, 60, 2–33; (w) Z. Zhang,
J.-H. Ye, T. Ju, L.-L. Liao, H. Huang, Y.-Y. Gui, W.-J. Zhou
and D.-G. Yu, ACS Catal., 2020, 10, 10871–10885;
(x) S. Pradhan, S. Roy, B. Sahoo and I. Chatterjee, Chem. –
Eur. J., 2021, 27, 2254–2269.
7 (a) V. R. Yatham, Y. Shen and R. Martin, Angew. Chem., Int.
Ed., 2017, 56, 10915–10919; (b) J. H. Ye, M. Miao,
H. Huang, S. S. Yan, Z. B. Yin, W. J. Zhou and D. G. Yu,
Angew. Chem., Int. Ed., 2017, 56, 15416–15420; (c) J. Hou,
A. Ee, H. Cao, H. W. Ong, J. H. Xu and J. Wu, Angew. Chem.,
Int. Ed., 2018, 57, 17220–17224; (d) J. Hou, A. Ee, W. Feng,
J. H. Xu, Y. Zhao and J. Wu, J. Am. Chem. Soc., 2018, 140,
5257–5263; (e) Q. Fu, Z. Y. Bo, J. H. Ye, T. Ju, H. Huang,
and S. H. Gellman, J. Am. Chem. Soc., 2009, 131, 16018–
16020; (b) L. Mathieu, B. Legrand, C. Deng, L. Vezenkov,
E. Wenger, C. Didierjean, M. Amblard, M. C. Averlant-Petit,
N. Masurier, V. Lisowski, J. Martinez and L. T. Maillard,
Angew. Chem., Int. Ed., 2013, 52, 6006–6010; (c) B. F. Fisher,
L. Guo, B. S. Dolinar, I. A. Guzei and S. H. Gellman, J. Am.
Chem. Soc., 2015, 137, 6484–6487; (d) C. M. Grison,
J. A. Miles, S. Robin, A. J. Wilson and D. J. Aitken, Angew.
Chem., Int. Ed., 2016, 55, 11096–11100; (e) H. Awada,
C. M. Grison, F. Charnay-Pouget, J. P. Baltaze, F. Brisset,
R. Guillot, S. Robin, A. Hachem, N. Jaber, D. Naoufal,
O. Yazbeck and D. J. Aitken, J. Org. Chem., 2017, 82, 4819–
4828; (f) R. Misra, S. Dey, R. M. Reja and H. N. Gopi,
Angew. Chem., Int. Ed., 2018, 57, 1057–1061; (g) Y. H. Shin
and S. H. Gellman, J. Am. Chem. Soc., 2018, 140, 1394–
1400; (h) M. Simon, L. M. A. Ali, K. El Cheikh, J. Aguesseau,
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6301–6312 | 6311

View Article Online
Paper
M. Gary-Bobo, M. Garcia, A. Morere and L. T. Maillard,
Organic & Biomolecular Chemistry
C. S. Elmore, F. Taran, A. Sallustrau and D. Audisio, ACS
Catal., 2021, 11, 2968–2976; (e) D. Kong, M. Munch,
Q. Qiqige, C. J. C. Cooze, B. H. Rotstein and R. J. Lundgren,
Chemistry, 2018, 24, 11426–11432; (i) Y. Wan, J. P. Baltaze,
C. Kouklovsky, E. Miclet and V. Alezra, J. Pept. Sci., 2019,
25, e3143.
J.
Am.
Chem.
Soc.,
2021,
143,
2200–2206;
11 (a) Y. Miyake, K. Nakajima and Y. Nishibayashi, J. Am.
Chem. Soc., 2012, 134, 3338–3341; (b) X. Dai, D. Cheng,
(f) K. C. Cartwright and J. A. Tunge, Chem. Sci., 2020, 11,
8167–8175.
B. Guan, W. Mao, X. Xu and X. Li, J. Org. Chem., 2014, 79, 13 (a) B. A. Sim, D. Griller and D. D. M. Wayner, J. Am.
7212–7219; (c) K. Miyazawa, T. Koike and M. Akita, Adv.
Synth. Catal., 2014, 356, 2749–2755; (d) L. R. Espelt,
I. S. McPherson, E. M. Wiensch and T. P. Yoon, J. Am.
Chem. Soc., 1989, 111, 754–755; (b) D. D. M. Wayner,
D. J. McPhee and D. Griller, J. Am. Chem. Soc., 1988, 110,
132–137.
Chem. Soc., 2015, 137, 2452–2455; (e) D. Lenhart, A. Bauer, 14 (a) D. D. M. Wayner, J. J. Dannenberg and D. Griller, Chem.
A. Pothig and T. Bach, Chemistry, 2016, 22, 6519–6523;
(f) J. J. Murphy, D. Bastida, S. Paria, M. Fagnoni and
P. Melchiorre, Nature, 2016, 532, 218–222; (g) S. X. Lin,
Phys. Lett., 1986, 131, 189–191; (b) K. Nakajima, Y. Miyake
and Y. Nishibayashi, Acc. Chem. Res., 2016, 49, 1946–
1956.
G. J. Sun and Q. Kang, Chem. Commun., 2017, 53, 7665– 15 H. Huang, C. Yu, Y. Zhang, Y. Zhang, P. S. Mariano and
7668; (h) J. Ma, J. Lin, L. Zhao, K. Harms, M. Marsch, X. Xie W. Wang, J. Am. Chem. Soc., 2017, 139, 9799–9802.
and E. Meggers, Angew. Chem., Int. Ed., 2018, 57, 11193– 16 (a) J. Caruano, G. G. Muccioli and R. Robiette, Org. Biomol.
11197; (i) J. B. McManus, N. P. R. Onuska and
D. A. Nicewicz, J. Am. Chem. Soc., 2018, 140, 9056–9060;
( j) J. Ye, I. Kalvet, F. Schoenebeck and T. Rovis, Nat. Chem.,
Chem., 2016, 14, 10134–10156; (b) F. I. Saldívar-González,
E. Lenci, A. Trabocchi and J. L. Medina-Franco, RSC Adv.,
2019, 9, 27105–27116.
2018, 10, 1037–1041; (k) M. A. Ashley, C. Yamauchi, 17 (a) M. R. Emmett, H. K. Grover and M. A. Kerr, J. Org.
J. C. K. Chu, S. Otsuka, H. Yorimitsu and T. Rovis, Angew.
Chem., 2019, 58, 4002–4006.
Chem., 2012, 77, 6634–6637; (b) S. M. Bronner and
R. H. Grubbs, Chem. Sci., 2014, 5, 101–106.
12 (a) K. Donabauer, M. Maity, A. L. Berger, G. S. Huff, 18 (a) O. Cussó, X. Ribas, J. Lloret-Fillol and M. Costas, Angew.
S. Crespi and B. König, Chem. Sci., 2019, 10, 5162–5166;
(b) Q. Y. Meng, T. E. Schirmer, A. L. Berger, K. Donabauer
and B. König, J. Am. Chem. Soc., 2019, 141, 11393–11397;
Chem., Int. Ed., 2015, 54, 2729–2733; (b) M. D. Greenhalgh
and S. P. Thomas, J. Am. Chem. Soc., 2012, 134, 11900–
11903.
(c) S. Grotjahn and B. König, Org. Lett., 2021, 23, 3146; 19 R. S. Lewis, M. F. Wisthoff, J. Grissmerson and W. J. Chain,
(d) V. Babin, A. Talbot, A. Labiche, G. Destro, A. D. Vecchio, Org. Lett., 2014, 14, 3832–3835.
6312 | Org. Biomol. Chem., 2021, 19, 6301–6312
This journal is © The Royal Society of Chemistry 2021