Synthesis of γ-Amino Esters by Copper-Catalyzed Intermolecular 1,2-Aminoalkylation of Alkenes with Amines and α-Bromoalkyl Esters

Article abstract of DOI:10.1055/s-0036-1591903

A new copper-catalyzed intermolecular 1,2-aminoalkylation of alkenes with α-bromoalkyl esters and amines for the synthesis of γ-amino esters is described. Employing the Cu(OTf) ₂ and 2,2′-bipyridine catalytic system, the three-component reaction allows the formation of two new chemical bonds, including one C-C bond and one C-N bond, in a single reaction, and represents a new alkene difunctionalization using a radical strategy.

Full text of DOI:10.1055/s-0036-1591903

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
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G.-H. Pan et al.
Paper
Synthesis
Synthesis of γ-Amino Esters by Copper-Catalyzed Intermolecular
1,2-Aminoalkylation of Alkenes with Amines and α-Bromoalkyl
Esters
Gao-Hui Pan
Ren-Jie Song*
Ye-Xiang Xie
Shenglian Luo
Jin-Heng Li*
R4
R5
Cu(OTf)2
2,2'-bipyridine
R1
R2
CO2R3
N
R1
R2
CO2R3
HNR4R5
Br
+
+
K2CO3
MeCN, 120 °C, 16 h
Ar
Ar
25 examples, up to 78% yield
Key Laboratory of Jiangxi Province for Persistent Pollutants
Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, P. R. of China
srj0731@hnu.edu.cn
jhli@hnu.edu.cn
Received: 17.11.2017
Accepted after revision: 03.01.2018
Published online: 24.01.2018
interest in the difunctionalization of alkenes, we herein re-
port a new copper-catalyzed difunctionalization of alkenes
with α-bromoalkyl esters and amines to synthesize γ-ami-
no esters (Scheme 1, b). This three-component multicom-
ponent reaction allows the formation of two new chemical
bonds, including one C–C bond and one C–N bond, in a sin-
gle reaction through intermolecular addition across alkene
with α-bromoalkyl esters7 followed by nucleophilic dis-
placement by amines.8
DOI: 10.1055/s-0036-1591903; Art ID: ss-2017-h0735-op
Abstract A new copper-catalyzed intermolecular 1,2-aminoalkylation
of alkenes with α-bromoalkyl esters and amines for the synthesis of
γ-amino esters is described. Employing the Cu(OTf)2 and 2,2′-bipyridine
catalytic system, the three-component reaction allows the formation of
two new chemical bonds, including one C–C bond and one C–N bond,
in a single reaction, and represents a new alkene difunctionalization us-
ing a radical strategy.
a) Previous work: Radical-mediated oxidative carboamination between alkenes
Key words copper, aminoalkylation, alkenes, γ-amino esters, α-bromo-
alkyl esters
R5
R2
R1
R6
Fe(OTf)3 or FeCl3
Ag2CO3
R4
R2
N
R4
R3
H
HNR5R6
+
+
R1
CN
120 °C, 24 h
CN
R3
γ-Amino esters have proven to be an important struc-
tural motif in bioactive natural products and pharmaceuti-
cals, and they are as well synthetically versatile intermedi-
ates for chemical synthesis.1,2 Most importantly, numerous
γ-amino ester-based molecules display high bioactivity
themselves in the treatment of epilepsy, HIV, neurodegen-
erative diseases, allergic disease, and depression. For these
reasons, increased attention has been directed to develop
efficient methods for accessing the γ-amino ester core.2,3
Classical synthetic routes to γ-amino esters predominantly
rely on the intermolecular 1,2-carboamination between a
carboxylic group and an amine or an amine precursor, but
available transformations still suffer from limited substrate
scope, the requirement of expensive catalysts, and/or
multistep processes.4 Despite significant progress in the
field, new methods for the synthesis of linear γ-amino
esters remain a great challenge.
b) This work: Copper-catalyzed 1,2-aminoalkylation of alkenes
R4
Ar
R5
Cu(OTf)2
2,2'-bipyridine
R1
R2
CO2R3
N
R1
R2
CO2R3
HNR4R5
+
Br
+
K2CO3
MeCN, 120 °C, 16 h
Ar
1
3
4
2
Scheme 1 1,2-Aminoalkylation of alkenes
We began our studies by treating 1-methoxy-4-vinyl-
benzene (1a) with methyl 2-bromopropanoate (2a) and
4-methoxyaniline (3a) (Table 1). Screening of various reac-
tion parameters demonstrated that alkene 1a reacted with
bromide 2a, amine 3a, 10 mol% of Cu(OTf)2, 20 mol% of
2,2′-bipyridine (L1), and 2 equivalents of K2CO3 in MeCN at
120 °C for 24 hours affording a satisfactory yield of the de-
sired product 4aaa (75% yield; Table 1, entry 1). The results
showed that both Cu(OTf)2 and K2CO3 are necessary, as the
reaction could not occur in the absence of either Cu(OTf)2
or K2CO3 (entries 2 and 3). It was noted that without ligands
the reaction delivered 4aaa in a lower yield (entry 4). Thus,
the effect of ligands was examined, and control experi-
ments revealed 2,2′-bipyridine (L1) as the preferred ligand
1,2-Carboamination reaction has attracted much atten-
tion due to the high step- and atom-economy.4c,5 Recently,
we reported an oxidative radical 1,2-carboamination of
alkenes with alkyl nitriles and amines for the synthesis
γ-amino alkyl nitriles (Scheme 1, a).6 In continuation of our
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G.-H. Pan et al.
Paper
Synthesis
compared to 1,10-phenanthroline (Phen; L2), N1,N1,N2,N2-
tetramethylethane-1,2-diamine (TMEDA; L3) and triphen-
ylphosphine (PPh3, L4) (entries 1 and 4–7). Although other
Cu catalysts, including CuBr2, CuOTf, CuI, CuBr, and CuCl,
displayed high activity, they were all less efficient than
Cu(OTf)2 (entries 8–12). Two other bases, Na2CO3 and
Cs2CO3, had lower reactivity (entries 13 and 14). Screening
on the amount of the Cu(OTf)2 and ligand L1 system
showed that a lower or a higher amount had a negative ef-
fect on the reaction (entries 15 and 16). We found that oth-
er polar solvents (e.g. 1,4-dioxane or DCE) were also highly
reactive (entries 17 and 18), but a nonpolar solvent, tolu-
ene, resulted in trace yield of 4aaa (entry 19). A lower tem-
perature (100 °C) slightly decreased the yield of 4aaa to 69%
(entry 20). However, a higher temperature (130 °C) disfa-
vored the formation of 4aaa because of the generation of
the side-product, 1,5-bis(4-methoxyphenyl)-3-methyl-
pyrrolidin-2-one (5aaa) (entry 21).
Table 1 Optimization of the Reaction Conditionsa
MeO
NH2
NH CO2Me
[Cu]/L
Br
+
+
base, solvent
CO2Me
2a
OMe
OMe
MeO
3a
1a
4aaa
Ph
Ph
N
N
P
Ph
N
N
N1,N1,N2,N2-tetramethyl-
ethane-1,2-diamine, L3
N
N
2,2'-bipyridine, L1
1,10-phenanthroline, L2
triphenylphosphine, L4
Entry
[Cu] (mol%)
L (mol%)
Base (equiv)
Solvent
Yield (%)b
1
2
Cu(OTf)2 (10)
–
L1 (20)
L1 (20)
L1 (20)
–
K2CO3 (2)
K2CO3 (2)
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
75
0
3
Cu(OTf)2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
CuBr2 (10)
0
4
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
Na2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
5
5
L2 (20)
L3 (20)
L4 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (10)
L1 (40)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
L1 (20)
65
30
0
6
7
8
44
45
73
72
20
43
25
59
50
57
71
trace
69
49
9
CuOTf (10)
CuI (10)
10
11
12
13
14
15
16
17
18
19
20c
21d
CuBr (10)
CuCl (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (20)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
1,4-dioxane
DCE
toluene
MeCN
MeCN
a Reaction conditions: 1a (0.2 mmol), 2a (2 equiv), 3a (2 equiv), [Cu], ligand, and solvent (2 mL) at 120 °C under argon atmosphere for 16 h. The dr value of 4aaa
is 2:1 as determined by 1H NMR analysis of the crude product.
b Isolated yield.
c At 100 °C.
d At 130 °C. A side-product, 1,5-bis(4-methoxyphenyl)-3-methylpyrrolidin-2-one (5aaa), was obtained in 23% yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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With the optimal conditions in hand, the generality of
this three-component reaction was next evaluated with re-
spect to styrenes 1, α-bromoalkyl esters 2, and amines 3
(Scheme 2). Surprisingly, employing other styrenes, includ-
ing 1-methoxy-3-vinylbenzene (1b), 1-methyl-4-vinylben-
zene (1c), and styrene (1d), the reaction afforded pyrroli-
din-2-ones 5baa–daa as the major products, and not the
expected γ-amino esters 4. Notably, the reaction of 1-me-
thoxy-4-vinylbenzene (1a) with a wide range of amines
3b–m still succeeded in accessing the desired γ-amino
esters 4aab–aam in moderate to good yields. Primary aryl-
amines 3b–e were smoothly converted into 4aab–aae in
49–78% yields. Likewise, a wide range of symmetrical and
unsymmetrical secondary amines 3f–i and N-methylben-
zenesulfonamide (3j) were highly reactive to access 4aaf–
aaj in synthetically useful yields. Gratifyingly, the reaction
R4
R5
Cu(OTf)2 (10 mol%)
2,2'-bipyridine (20 mol%)
R1
R2
CO2R3
N
R1
R2
CO2R3
HNR4R5
+
Br
+
Ar
K2CO3 (2 equiv)
MeCN, 120 °C, 16 h
Ar
2
3
4
1
MeO
MeO
MeO
MeO
O
O
O
NH
N
N
N
CO2Me
MeO
5baa, 39%, 51%a (1.2:1)
5caa, 60%a (1.2:1)
5daa, 55%a (1.2:1)
4aab, 70% (1.2:1)
Ph
NH
NH
NH
CO2Me
CO2Me
CO2Me
MeO
MeO
MeO
MeO
4aac, 49% (1.2:1)
4aad, 57% (1.2:1)
Bn Bn
4aae, 78% (1.2:1)
Ph
Ph
N
N
N
CO2Me
CO2Me
CO2Me
MeO
MeO
MeO
4aah, 58% (1.2:1)
4aaf, 51% (1.1:1)
4aag, 58% (1.6:1)
O
Ph
N
PhO2S
N
N
CO2Me
CO2Me
CO2Me
MeO
4aai, 67% (1.3:1)
4aaj, 56% (2:1)
MeO
MeO
4aak, 41% (1:1)
Ph
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
MeO
MeO
4aal, 40% (1:1)
4aam, 57% (1.2:1)
4bai, 57% (1.5:1)
Ph
Ph
N
Ph
N
Ph
N
N
CO2Me
CO2Me
CO2Me
OMe
4eai, 51% (1.6:1)
MeO
4dai, 46%b
4fai, trace
4gai, 55% (1.6:1)
O
MeO
MeO
MeO
N
NH
NH
R
CN
CO2Me
CO2Et
R = CO2Et, 4aca, 50%
R = Me, 4ada, 64%
MeO
MeO
4aba, 55% (1.6:1)
4aek, 71% (1.3:1)
Scheme 2 The alkene aminoalkylation toward γ-amino esters. Reagents and conditions: 1 (0.2 mmol), 2 (2 equiv), amine 3 (2 equiv), Cu(OTf)2 (10 mol%),
L1 (20 mol%), K2CO3 (2 equiv), MeCN (2 mL), 120 °C under argon atmosphere for 16 h. The dr value is given in the parenthesis as determined by 1H NMR
analysis of the crude product. a Reaction was conducted at 130 °C. b Some side-products, especially methyl N-methyl-N-phenylalaninate that was gener-
ated from the reaction between bromide 2a and amine 3i, were observed by GC-MS analysis.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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G.-H. Pan et al.
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Synthesis
was applicable to secondary cyclic amines 3k–m, providing
4aak–aam in 40–57% yields. Notably, employing secondary
amine 3i, 1-methoxy-3-vinylbenzene (1b) could be
smoothly converted into the expected γ-amino ester 4bai.
Other arylalkenes, including styrene (1d), 1-methoxy-2-
vinylbenzene (1e), and 1-methoxy-4-(prop-1-en-1-yl)ben-
zene (1g) were suitable for producing γ-amino esters 4dai,
4eai, and 4gai, but aliphatic alkene 1f had no reactivity
(4fai). The aminoalkylation reaction was applicable to sec-
ondary α-bromoalkyl ester 2b and tertiary α-bromoalkyl
esters 2c,d, thus furnishing 4aba and 4aca,ada in moderate
yields. With α-bromobutyronitrile (1e) the reaction was
successful for preparing 4aek in good yield.
tained in the absence of amine 3a. The reaction between
product 8 and amine 3a was not successful under the opti-
mal conditions (Scheme 3, eq. 3).
Therefore, a possible mechanism is outlined in Scheme
4 for this 1,2-aminoalkylation of alkenes with α-bromoal-
kyl esters and amines on the basis of the experimental and
previous studies.6–8 First, the α-C(sp3)–Br bond of α-car-
bonyl alkyl bromide 2 was cleaved to generate the alkyl rad-
ical A in the presence of CuII species under heating condi-
tion via a single-electron transfer (SET) process. Oxidative
addition of the alkyl radical A to the C=C bond of alkenes 1
leads to the new radical intermediate B. Subsequent oxida-
tion of intermediate B by the active CuII species generates
the oxocarbenium ion intermediate C. Finally, nucleophilic
attack of intermediate C by amine 3 takes place to furnish
the desired γ-amino esters 4. In addition, the γ-amino
esters 4 get converted into pyrrolidine-2-ones 5 when
R4 = H under heating conditions.
As shown in Scheme 3, (1-cyclopropylvinyl)benzene
(1h) reacted with α-bromoalkyl ester 2a and amines 3a to
afford 4haa along with the monoalkylation/ring-open-
ing/cyclization product 6ha (Scheme 3, eq. 1).8g Notably,
the reaction of alkene 1a with ester 2a and amine 3a was
completely suppressed when using
a
stoichiometric
In summary, we have developed a new copper-cata-
lyzed intermolecular 1,2-aminoalkylation of alkenes with
α-bromoalkyl esters and amines for the synthesis of γ-ami-
no esters. Employing Cu(OTf)2 and 2,2′-bipyridine, the reac-
tion allows the formation of two new chemical bonds, in-
cluding one C–C bond and one C–N bond, in a single reac-
amount of radical inhibitors (3 equiv), including 2,2,6,6-te-
tramethylpiperidinooxy (TEMPO), 2,6-di-tert-butyl-4-
methylphenol (BHT), and hydroquinone (Scheme 3, eq. 2).
These results support the current reaction possessing a
free-radical process. However, an 82% yield of ethyl (E)-4-
(4-methoxyphenyl)-2,2-dimethylbut-3-enoate (8) was ob-
tion, using
a radical strategy, which features broad
substrate scope and excellent selectivity.
OMe
CO2Me
NH2
Cu(OTf)2 (10 mol%)
L1 (20 mol%)
Br
(1)
+
+
+
K2CO3 (2 equiv)
MeCN, 120 °C, 24 h
CO2Me
2a
Ph
NH CO2Me
OMe
Ph
1h
3a
6ha, 30%
4haa, 9%
MeO
Additive (3 equiv)
NH2
Cu(OTf)2 (10 mol%)
L1 (20 mol%)
NH
(2)
+
+
Br
K2CO3 (2 equiv)
MeCN, 120 °C, 24 h
CO2Me
CO2Me
2d
OMe
OMe
1a
MeO
3a
4ada
N
O
Yield of 4ada
Additive
TEMPO
2,6-di-tert-butyl-4-methylphenol (BHT)
O
trace
trace
trace
EtO
7 (85% yield)
hydroquinone
Cu(OTf)2 (10 mol%)
L1 (20 mol%)
CO2Me
MeO
+
Br
K2CO3 (2 equiv)
MeCN, 120 °C, 24 h
CO2Me
MeO
1a
2d
8 (82% yield)
MeO
NH2
(3)
Cu(OTf)2 (10 mol%)
L1 (20 mol%)
NH
CO2Me
+
K2CO3 (2 equiv)
MeCN, 120 °C, 24 h
CO2Me
MeO
OMe
MeO
8
3a
4ada (0%)
Scheme 3 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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G.-H. Pan et al.
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Synthesis
Ar
R1
R2
R1
R2
1
Br
COOR3
COOR3
CuIILnBr
OR3
2
A
NHR4R5
R1
R2
IILn
CuILn
O
3
L
OR3
O+
R4R5N
R4R5N
Ar
O
R1
Ar
Cu
R1
R2
B
R2
CuIILn-1Br
R5
N
R2
CuILn
R4 = H
R1 COOR3
L + base
base HBr
Ar
Ar
4
5
C
Scheme 4 Possible mechanism
13C NMR (100 MHz, CDCl3): δ = 177.2, 176.8, 158.6, 158.6, 147.2,
147.1, 135.5, 135.1, 129.0 (2 C), 127.3 (2 C), 117.2 (2 C), 114.0 (2 C),
113.3, 113.2, 56.0, 55.5, 55.2, 51.7 (2 C), 42.6, 42.1, 37.4, 36.4, 17.9,
17.6.
NMR spectroscopy was performed on a Bruker Avance spectrometer
operating at 400 MHz (1H NMR) and 100 MHz (13C NMR). Mass spec-
trometric analysis was performed by GC-MS analysis using a Shimad-
zu GCMS-QP2010 instrument and ESI-Q-TOF on a Bruker MicroQTOF-II
spectrometer.
LRMS (EI, 70 eV): m/z (%) = 313 (M+, 19), 212 (100), 161 (72).
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO3: 314.1751; found:
314.1753.
Copper-Catalyzed Synthesis of γ-Amino Esters 4; General Proce-
dure
To a Schlenk tube were added alkene 1 (0.2 mmol), α-bromoalkyl es-
ter 2 (0.4 mmol), amine 3 (0.4 mmol), Cu(OTf)2 (10 mol%), 2,2′-bipyri-
dine (L1; 20 mol%), K2CO3 (2 equiv), and MeCN (2 mL). Then the tube
was charged with argon, and the contents were stirred at 120 °C for
16 h until complete consumption of the starting materials as moni-
tored by TLC and/or GC-MS analysis. After completion of the reaction,
the contents were concentrated under vacuum, and the resulting res-
idue was purified by silica gel column chromatography (hexane/EtO-
Ac) to afford the desired γ-amino ester 4.
Methyl 4-(4-Methoxyphenyl)-2-methyl-4-(m-tolylamino)buta-
noate (4aac)
Yield: 32.0 mg (49%); yellow oil; dr = 1.2:1.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.21 (m, 2 H), 6.96 (t, J = 7.8 Hz, 1
H), 6.84 (d, J = 8.0 Hz, 2 H), 6.45 (d, J = 7.6 Hz, 1 H), 6.34 (s, 1 H), 6.30
(t, J = 7.4 Hz, 1 H), 4.36 (t, J = 7.0 Hz, 0.6 H), 4.31 (t, J = 7.2 Hz, 0.4 H),
4.04 (s, 0.8 H), 3.76 (s, 3 H), 3.67 (s, 1.3 H), 3.62 (s, 1.6 H), 2.60–2.51
(m, 1 H), 2.27–2.16 (m, 4 H), 1.87–1.81 (m, 0.6 H), 1.76–1.70 (m, 0.5
H), 1.21 (d, J = 7.2 Hz, 1.7 H), 1.18 (d, J = 6.8 Hz, 1.4 H).
13C NMR (100 MHz, CDCl3): δ = 177.2, 176.8, 158.6 (2 C), 147.2, 147.1,
138.7, 135.7, 135.3, 128.9, 127.3 (2 C), 118.2 (2 C), 114.2, 114.0 (3 C),
110.3, 110.2, 56.0, 55.4, 55.2, 51.7 (2 C), 42.6, 42.1, 37.4, 36.4, 21.6,
17.9, 17.6.
LRMS (EI, 70 eV): m/z (%) = 327 (M+, 8), 226 (100), 161 (66).
HRMS: (ESI) m/z [M + H]+ calcd for C20H26NO3: 328.1907; found:
Methyl 4-(4-Methoxyphenyl)-4-[(4-methoxyphenyl)amino]-2-
methylbutanoate (4aaa)
Yield: 51.5 mg (75%); yellow oil; dr = 2:1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.20 (m, 2 H), 6.83 (d, J = 8.0 Hz, 2
H), 6.67 (d, J = 8.4 Hz, 2 H), 6.48–6.44 (m, 2 H), 4.30–4.22 (m, 1 H),
3.76 (s, 3 H), 3.67 (s, 3 H), 3.66 (s, 1 H), 3.61 (s, 2 H), 2.60–2.53 (m, 1
H), 2.24–2.14 (m, 1 H), 1.87–1.80 (m, 0.7 H), 1.75–1.70 (m, 0.3 H),
1.20 (d, J = 7.2 Hz, 2 H), 1.17 (d, J = 7.2 Hz, 1 H).
328.1915.
13C NMR (100 MHz, CDCl3): δ = 177.2, 176.8, 158.6, 158.5, 151.9,
151.8, 141.4, 141.3, 135.7, 135.4, 127.4, 127.3, 114.7 (2 C), 114.4,
114.0, 113.9, 56.8, 56.4, 55.6, 55.1, 51.7, 51.6, 42.6, 42.1, 37.3, 36.4,
17.9, 17.6.
LRMS (EI, 70 eV): m/z (%) = 343 (M+, 28), 242 (62), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C20H26NO4: 344.1856; found:
Methyl 4-(4-Methoxyphenyl)-2-methyl-4-(o-tolylamino)buta-
noate (4aad)
Yield: 37.3 mg (57%); yellow oil; dr = 1.2:1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.21 (m, 2 H), 7.03–7.00 (m, 1 H),
6.96–6.91 (m, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.59–6.55 (m, 1 H), 6.39
(d, J = 8.0 Hz, 0.5 H), 6.34 (d, J = 8.0 Hz, 0.6 H), 4.43 (t, J = 6.8 Hz, 0.6 H),
4.39–4.36 (m, 0.5 H), 4.01 (s, 0.8 H), 3.76 (s, 3 H), 3.67 (s, 1.4 H), 3.62
(s, 1.7 H), 2.62–2.53 (m, 1 H), 2.32–2.24 (m, 1 H), 2.19 (m, 1.7 H), 2.18
(m, 1.3 H), 1.95–1.88 (m, 0.6 H), 1.80–1.74 (m, 0.5 H), 1.22 (d, J = 7.2
Hz, 1.7 H), 1.19 (d, J = 6.8 Hz, 1.4 H).
13C NMR (100 MHz, CDCl3): δ = 177.3, 177.0, 158.6 (2 C), 145.1, 144.9,
135.7, 135.1, 129.9 (2 C), 127.3, 127.2, 126.9 (2 C), 121.8, 121.7, 116.8,
116.7, 114.0 (2 C), 110.9, 110.8, 56.1, 55.4, 55.2, 51.7 (2 C), 42.7, 42.0,
37.6, 36.3, 18.2, 17.7, 17.6 (2 C).
344.1863.
Methyl 4-(4-Methoxyphenyl)-2-methyl-4-(phenylamino)buta-
noate (4aab)
Yield: 43.8 mg (70%); yellow oil; dr = 1.2:1.
1H NMR (400 MHz, CDCl3): δ = 7.23 (t, J = 7.0 Hz, 2 H), 7.07 (t, J = 7.6
Hz, 2 H), 6.84 (d, J = 8.0 Hz, 2 H), 6.62 (t, J = 7.4 Hz, 1 H), 6.52–6.49 (m,
2 H), 4.36 (t, J = 7.0 Hz, 0.6 H), 4.31 (t, J = 7.4 Hz, 0.5 H), 4.10 (s, 0.8 H),
3.76 (s, 3 H), 3.67 (s, 1.4 H), 3.62 (s, 1.6 H), 2.60–2.52 (m, 1 H), 2.27–
2.16 (m, 1 H), 1.89–1.82 (m, 0.6 H), 1.77–1.70 (m, 0.5 H), 1.21 (d, J =
6.8 Hz, 1.7 H), 1.18 (d, J = 6.8 Hz, 1.3 H).
LRMS (EI, 70 eV): m/z (%) = 327 (M+, 24), 226 (83), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C20H26NO3: 328.1907; found:
328.1921.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

F
G.-H. Pan et al.
Paper
Synthesis
Methyl 4-([1,1′-Biphenyl]-2-ylamino)-4-(4-methoxyphenyl)-2-
methylbutanoate (4aae)
H), 3.62 (s, 1.6 H), 2.58–2.55 (m, 0.6 H), 2.49–2.39 (m, 1.5 H), 2.10–
2.03 (m, 0.6 H), 1.97–1.91 (m, 0.4 H), 1.19 (d, J = 6.4 Hz, 1.4 H), 1.15 (d,
J = 6.8 Hz, 1.7 H).
Yield: 60.7 mg (78%); yellow oil; dr = 1.2:1.
13C NMR (100 MHz, CDCl3): δ = 176.9, 176.7, 158.7, 158.6, 146.6,
146.5, 132.9, 132.4, 129.5, 129.0 (2 C), 123.1, 122.8, 121.7, 121.6,
113.4 (2 C), 59.1, 58.8, 55.1 (2 C), 51.6 (2 C), 36.5 (2 C), 35.7, 35.6, 18.0,
17.5.
(EI, 70 eV): m/z (%) = 389 (M+, 8), 221 (65), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO3: 390.2064; found:
1H NMR (400 MHz, CDCl3): δ = 7.50–7.43 (m, 4 H), 7.37 (t, J = 7.0 Hz, 1
H), 7.19–7.15 (m, 2 H), 7.08–7.03 (m, 2 H), 6.83 (d, J = 8.4 Hz, 2 H),
6.69 (t, J = 7.4 Hz, 1 H), 6.52 (d, J = 8.0 Hz, 0.5 H), 6.47 (d, J = 8.4 Hz, 0.6
H), 4.37–4.29 (m, 2 H), 3.75 (s, 3 H), 3.57 (s, 1.4 H), 3.54 (s, 1.7 H),
2.46–2.39 (m, 1 H), 2.12–2.06 (m, 1 H), 1.70–1.60 (m, 1 H), 1.12 (t, J =
7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.6, 176.5, 158.6 (2 C), 143.9, 143.8,
139.5 (2 C), 135.3, 135.1, 130.1, 130.0, 129.3 (2 C), 128.9, 128.4, 127.8,
127.7, 127.3, 127.2, 116.9, 114.0 (2 C), 111.7, 111.6, 55.9, 55.7, 55.1,
51.6 (2 C), 42.4, 42.3, 36.9, 36.4, 17.7, 17.6.
390.2072.
Methyl 4-(4-Methoxyphenyl)-2-methyl-4-[methyl(phenyl)ami-
no]butanoate (4aai)
LRMS (EI, 70 eV): m/z (%) = 389 (M+, 18), 288 (100), 161 (67).
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO3: 390.2064; found:
Yield: 43.8 mg (67%); yellow oil; dr = 1.3:1.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.20 (m, 2 H), 7.15 (d, J = 8.4 Hz, 1
H), 7.12 (d, J = 8.4 Hz, 1 H), 6.85–6.78 (m, 4 H), 6.74–6.69 (m, 1 H),
5.08–5.00 (m, 1 H), 3.77 (s, 3 H), 3.56 (s, 1.3 H), 3.54 (s, 1.7 H), 2.61 (s,
1.7 H), 2.57 (s, 1.3 H), 2.54–2.51 (m, 1 H), 2.49–2.42 (m, 1 H), 2.03–
1.96 (m, 1 H), 1.23 (t, J = 7.2 Hz, 3 H).
390.2071.
Methyl 4-(Diallylamino)-4-(4-methoxyphenyl)-2-methylbutanoate
(4aaf)
13C NMR (100 MHz, CDCl3): δ = 176.8 (2 C), 158.6, 158.5, 150.6, 150.5,
132.6, 132.4, 129.1 (2 C), 128.2, 116.9, 116.8, 113.6 (2 C), 113.4, 113.2,
58.8, 58.7, 55.2, 51.5 (2 C), 37.1, 36.4, 35.5 (2 C), 31.5, 31.4, 18.2, 17.4.
LRMS (EI, 70 eV): m/z (%) = 327 (M+, 14), 221 (47), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C22H26NO3: 328.1907; found:
Yield: 32.3 mg (51%); yellow oil; dr = 1.1:1.
1H NMR (400 MHz, CDCl3): δ = 7.13–7.10 (m, 2 H), 6.86 (d, J = 8.0 Hz, 2
H), 5.84–5.73 (m, 2 H), 5.17–5.09 (m, 4 H), 3.81 (s, 3 H), 3.78–3.72 (m,
1 H), 3.67 (s, 1.6 H), 3.60 (s, 1.4 H), 3.29–3.22 (m, 2 H), 2.69–2.45 (m, 4
H), 2.14–2.07 (m, 0.6 H), 2.00–1.93 (m, 0.5 H), 1.16–1.14 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.5, 177.1, 158.6 (2 C), 137.2, 130.8,
130.4, 129.8, 129.7, 116.9, 116.7, 113.3 (2 C), 60.1, 59.7, 55.2, 52.6,
52.5, 51.4, 37.4, 36.8, 36.3, 35.8, 17.7, 17.4.
328.1913.
Methyl 4-(4-Methoxyphenyl)-2-methyl-4-(N-methylphenylsul-
fonamido)butanoate (4aaj)
LRMS (EI, 70 eV): m/z (%) = 317 (M+, 1), 216 (100), 161 (26).
HRMS (ESI): m/z [M + H]+ calcd for C19H28NO3: 318.2064; found:
Yield: 43.8 mg (56%); yellow oil; dr = 2:1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.2 Hz, 2 H), 7.56–7.51 (m, 1
H), 7.48 (m, 2 H), 7.05 (t, J = 7.6 Hz, 2 H), 6.75 (t, J = 7.8 Hz, 2 H), 5.17–
5.10 (m, 1 H), 3.76 (s, 3 H), 3.69 (s, 1 H), 3.64 (s, 2 H), 2.61 (s, 1.9 H),
2.60 (s, 1.0 H), 2.51–2.42 (m, 1 H), 2.39–2.30 (m, 1 H), 1.81–1.74 (m,
0.4 H), 1.70–1.63 (m, 0.7 H), 1.23 (d, J = 6.8 Hz, 1 H), 1.17 (d, J = 7.2 Hz,
2 H).
13C NMR (100 MHz, CDCl3): δ = 176.5, 176.2, 159.1 (2 C), 140.1 (2 C),
132.3 (2 C), 129.5, 129.3, 129.1, 129.0, 128.9, 128.8, 127.1 (2 C), 113.7,
113.6, 57.6, 55.2, 51.7 (2 C), 36.5, 36.2, 34.6, 34.2, 28.8, 28.7, 17.2,
17.1.
318.2073.
Methyl 4-(Dibenzylamino)-4-(4-methoxyphenyl)-2-methylbuta-
noate (4aag)
Yield: 48.4 mg (58%); yellow oil; dr = 1.6:1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.35 (m, 4 H), 7.32–7.28 (m, 4 H),
7.24–7.19 (m, 2 H), 7.15–7.13 (m, 2 H), 6.93–6.90 (m, 2 H), 3.83 (s, 3
H), 3.79–3.74 (m, 2 H), 3.72–3.70 (m, 0.6 H), 3.64 (t, J = 7.6 Hz, 0.4 H),
3.55 (s, 1.2 H), 3.50 (s, 1.9 H), 3.13 (d, J = 13.6 Hz, 1.3 H), 3.07 (d, J =
13.2 Hz, 0.8 H), 2.71–2.63 (m, 1 H), 2.56–2.49 (m, 0.4 H), 2.28–2.21
(m, 0.6 H), 2.05–1.98 (m, 0.6 H), 1.73–1.66 (m, 0.4 H), 1.07 (d, J = 6.8
Hz, 1.9 H), 0.95 (d, J = 6.8 Hz, 1.2 H).
HRMS (ESI): m/z calcd for C20H26NO5S [M + H]+ : 392.1526; found:
392.1533.
13C NMR (100 MHz, CDCl3): δ = 177.3, 176.9, 158.7, 158.6, 140.1,
130.1 (2 C), 130.0, 129.8, 128.9, 128.7, 128.2 (2 C), 126.8, 126.7, 113.3
(2 C), 58.8, 58.4, 55.2, 53.7, 53.5, 51.5, 51.4, 36.5 (2 C), 35.8, 35.1, 17.6,
16.9.
LRMS (EI, 70 eV): m/z (%) = 417 (M+, 1), 316 (100), 91 (80).
HRMS (ESI): m/z [M + H]+ calcd for C27H32NO3: 418.2377; found:
Methyl 4-(4-Methoxyphenyl)-2-methyl-4-morpholinobutanoate
(4aak)
Yield: 25.2 mg (41%); yellow oil; dr = 1:1.
1H NMR (400 MHz, CDCl3): δ = 7.11 (t, J = 9.2 Hz, 2 H), 6.86 (d, J = 8.4
Hz, 2 H), 3.80 (s, 3 H), 3.68 (s, 1.5 H), 3.65–3.62 (m, 4 H), 3.56 (s, 1.5
H), 3.34–3.31 (m, 0.5 H), 3.26 (t, J = 7.4 Hz, 0.5 H), 2.49–2.43 (m, 0.5
H), 2.38–2.29 (m, 5 H), 2.15–2.08 (m, 0.5 H), 2.04–1.97 (m, 0.5 H),
1.60–1.54 (m, 0.6 H), 1.13 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.2, 176.9, 158.9, 158.8, 130.9,
130.3, 129.8, 129.6, 113.5, 113.4, 67.9, 67.2 (2 C), 55.2, 51.5 (2 C), 50.6,
50.5, 37.4, 36.6, 36.2, 35.6, 18.4, 16.8.
418.2386.
Methyl 4-(Diphenylamino)-4-(4-methoxyphenyl)-2-methylbuta-
noate (4aah)
Yield: 45.1 mg (58%); yellow oil; dr = 1.2:1.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.16 (m, 4 H), 7.11 (d, J = 8.4 Hz, 1
H), 7.01 (d, J = 8.4 Hz, 1 H), 6.95–6.91 (m, 2 H), 6.82–6.73 (m, 6 H),
5.37 (t, J = 7.8 Hz, 0.6 H), 5.29–5.26 (m, 0.5 H), 3.76 (s, 3 H), 3.67 (s, 1.4
LRMS (EI, 70 eV): m/z (%) = 307 (M+, 1), 206 (100), 161 (16).
HRMS (ESI): m/z [M + H]+ calcd for C17H26NO4: 308.1856, found
308.1865.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
G.-H. Pan et al.
Paper
Synthesis
Methyl 4-[3,4-Dihydroquinolin-1(2H)-yl]-4-(4-methoxyphenyl)-2-
methylbutanoate (4aal)
13C NMR (100 MHz, CDCl3): δ = 176.9, 176.8, 157.6, 157.2, 150.4,
150.3, 129.4, 128.8, 128.7, 128.2, 128.1, 127.3, 127.1, 120.2, 120.0,
116.5, 116.4, 113.4, 113.1, 110.7, 110.6, 55.3, 55.2, 54.0, 53.9, 51.4,
51.4, 37.0, 36.6, 35.6, 34.8, 31.9, 31.7, 17.6, 17.0.
LRMS (EI, 70 eV): m/z (%) = 327 (M+, 19), 221 (45), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C22H25NO3: 328.1907; found:
Yield: 28.2 mg (40%); yellow oil; dr = 1:1.
1H NMR (400 MHz, CDCl3): δ = 7.21 (t, J = 8.4 Hz, 2 H), 7.07–7.00 (m, 1
H), 6.94 (d, J = 7.2 Hz, 1 H), 6.84 (t, J = 9.4 Hz, 2.5 H), 6.72 (d, J = 8.4 Hz,
0.5 H), 6.58–6.53 (m, 1 H), 5.10–5.06 (m, 1 H), 3.78 (s, 3 H), 3.60 (s, 1.5
H), 3.58 (s, 1.5 H), 3.15–3.05 (m, 1 H), 2.99–2.89 (m, 1 H), 2.73–2.68
(m, 2 H), 2.62–2.55 (m, 1 H), 2.51 (m, 1 H), 2.04–1.97 (m, 1 H), 1.88–
1.81 (m, 1 H), 1.77–1.68 (m, 1 H), 1.59 (s, 1 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.9 (2 C), 158.6, 158.5, 145.8, 145.7,
132.6 (2 C), 129.3, 128.4 (2 C), 127.1, 127.0, 122.9, 122.6, 115.5, 115.4,
113.7 (2 C), 110.9 (2 C), 56.6, 56.3, 55.2, 51.6 (2 C), 42.5, 42.0, 36.7,
36.3, 34.6 (2 C), 28.6, 28.5, 22.0, 21.9, 18.1, 17.3.
328.1913.
Methyl 4-(4-Methoxyphenyl)-2,3-dimethyl-4-[methyl(phe-
nyl)amino]butanoate (4gai)
Yield: 37.5 mg (55%); yellow oil; d.r. = 1.6:1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.19 (m, 2 H), 7.13 (d, J = 8.0 Hz,
1.2 H), 7.05 (d, J = 7.8 Hz, 0.8 H), 6.92 (d, J = 8.0 Hz, 0.8 H), 6.85–6.80
(m, 2.4 H), 6.76 (d, J = 8.2 Hz, 1 H), 6.71–6.67 (m, 1 H), 5.23 (d, J = 11.2
Hz, 0.6 H), 4.96 (d, J = 11.2 Hz, 0.4 H), 3.76 (s, 1.8 H), 3.74 (s, 1.2 H),
3.68 (s, 1.9 H), 3.62 (s, 1.1 H), 3.10–3.04 (m, 0.4 H), 2.55–2.53 (m, 3 H),
2.50–2.41 (m, 1.6 H), 1.28 (d, J = 7.2 Hz, 1.2 H), 1.18 (d, J = 7.2 Hz, 1.8
H), 1.00 (d, J = 6.8 Hz, 1.8 H), 0.86 (d, J = 6.8 Hz, 1.2 H).
13C NMR (100 MHz, CDCl3): δ = 175.5, 175.0, 158.6, 158.5, 150.8,
150.6, 130.6, 130.0, 129.1, 129.0, 128.9, 128.8, 117.6, 116.6, 115.3,
113.6, 113.5, 113.3, 66.0, 64.3, 55.1, 55.1, 51.3, 51.2, 40.1, 39.1, 38.2,
37.5, 31.3, 30.8, 16.0, 15.8, 13.3, 12.3.
LRMS (EI, 70 eV): m/z (%) = 353 (M+, 19), 271 (49), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C22H28NO3: 354.2064; found:
354.2074.
Methyl 4-(Indolin-1-yl)-4-(4-methoxyphenyl)-2-methylbuta-
noate (4aam)
Yield: 38.6 mg (57%); yellow oil; dr = 1.2:1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.08 (m, 2 H), 7.06–6.97 (m, 2 H),
6.82 (d, J = 7.6 Hz, 2 H), 6.59–6.54 (m, 1.5 H), 6.49 (d, J = 8.0 Hz, 0.6 H),
4.74–4.67 (m, 1 H), 3.76 (s, 3 H), 3.59 (s, 1.7 H), 3.55 (s, 1.4 H), 3.41–
3.35 (m, 1 H), 3.17–3.10 (m, 0.6 H), 3.06–3.01 (m, 0.5 H), 2.93–2.82
(m, 2 H), 2.63–2.53 (m, 1 H), 2.51–2.48 (m, 0.5 H), 2.39–2.32 (m, 0.6
H), 2.09–2.03 (m, 0.6 H), 1.91–1.88 (m, 0.4 H), 1.25–1.21 (m, 3 H).
LRMS (EI, 70 eV): m/z (%) = 341 (M+, 3.2), 226 (100), 175 (11).
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO3: 342.2064; found:
342.2080.
13C NMR (100 MHz, CDCl3): δ = 177.0, 176.7, 158.7 (2 C), 151.3, 151.2,
131.6, 131.4, 129.6, 129.5, 128.9 (2 C), 127.2, 124.5, 124.4, 116.7,
116.6, 113.6, 106.5, 106.4, 56.0, 55.7, 55.1, 51.5, 51.4, 46.5, 46.1, 37.2,
36.5, 35.3, 34.9, 28.0 (2 C), 17.5, 17.4.
LRMS (EI, 70 eV): m/z (%) = 339 (M+, 22), 221 (46), 161 (100).
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO3: 340.1907; found:
Methyl 2-{2-(4-Methoxyphenyl)-2-[(4-methoxyphenyl)ami-
no]ethyl}hexanoate (4aba)
Yield: 42.4 mg (55%); yellow oil; dr = 1.6:1.
1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 8.4
Hz, 2 H), 6.67 (d, J = 8.0 Hz, 2 H), 6.47–6.44 (m, 2 H), 4.25–4.22 (m, 0.6
H), 4.20–4.16 (m, 0.4 H), 3.75 (s, 3 H), 3.67 (s, 4.2 H), 3.59 (s, 1.9 H),
2.60–2.52 (m, 0.6 H), 2.43–2.36 (m, 0.4 H), 2.20–2.11 (m, 1 H), 1.87–
1.74 (m, 1 H), 1.66–1.57 (m, 1 H), 1.54–1.42 (m, 1 H), 1.28–1.22 (m, 4
H), 0.89–0.83 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.9, 176.5, 158.5 (2 C), 151.8 (2 C),
141.5, 141.3, 135.6, 135.5, 127.3, 114.7, 114.6 (2 C), 114.4, 113.9 (2 C),
57.2, 56.6, 55.6, 55.1, 51.5, 51.4, 43.3, 42.3, 41.1, 40.9, 32.8, 32.5, 29.2
(2 C), 22.5 (2 C), 13.8 (2 C).
340.1916.
Methyl 4-(3-Methoxyphenyl)-2-methyl-4-[methyl(phenyl)ami-
no]butanoate (4bai)
Yield: 40.7 mg (57%); yellow oil; dr = 1.5:1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.19 (m, 3 H), 6.85 (s, 0.7 H), 6.83
(s, 0.5 H), 6.79–6.75 (m, 3 H), 6.74–6.69 (m, 1 H), 5.09–5.05 (m, 0.6 H),
5.03–5.01 (m, 0.4 H), 3.74 (s, 1.8 H), 3.73 (s, 1.2 H), 3.56 (s, 1.2 H), 3.53
(s, 1.7 H), 2.66 (s, 1.8 H), 2.62 (s, 1.2 H), 2.59–2.54 (m, 1 H), 2.50–2.41
(m, 1 H), 2.04–1.98 (m, 1 H), 1.25–1.21 (m, 3 H).
LRMS (EI, 70 eV): m/z (%) = 385 (M+, 36), 203 (100), 121 (67).
HRMS (ESI): m/z [M + H]+ calcd for C23H32NO4: 386.2326; found:
386.2332.
13C NMR (100 MHz, CDCl3): δ = 176.8, 176.7, 159.6, 150.5 (2 C), 142.5,
142.2, 129.3 (2 C), 129.1 (2 C), 119.4 (2 C), 117.0, 116.8, 113.4, 113.1
(2 C), 113.0, 112.0 (2 C), 59.3, 59.2, 55.1, 51.5 (2 C), 37.0, 36.3, 35.6,
35.5, 31.7, 31.6, 18.3, 17.3.
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO4: 358.2014; found:
358.2019.
Methyl 2-{2-(4-Methoxyphenyl)-2-[(4-methoxyphenyl)ami-
no]ethyl}hexanoate (4aca)
Yield: 42.9 mg (50%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.4
Hz, 2 H), 6.65 (d, J = 8.8 Hz, 2 H), 6.40 (d, J = 8.8 Hz, 2 H), 4.43–4.41 (m,
1 H), 4.21–4.16 (m, 2 H), 4.11–4.07 (m, 1 H), 4.01–3.97 (m, 1 H), 3.76
(s, 3 H), 3.67 (s, 3 H), 2.43–2.37 (m, 1 H), 2.21–2.16 (m, 1 H), 1.52 (s, 3
H), 1.22 (t, J = 7.0 Hz, 3 H), 1.15 (t, J = 7.0 Hz, 3 H).
Methyl 4-(2-Methoxyphenyl)-2-methyl-4-[methyl(phenyl)ami-
no]butanoate (4eai)
13C NMR (100 MHz, CDCl3): δ = 172.6 (2 C), 158.5, 151.7, 141.0, 136.1,
127.2, 114.7, 114.3, 113.9, 61.6, 61.5, 55.7, 55.2, 54.4, 52.8, 44.4, 20.4,
14.0, 13.9.
LRMS (EI, 70 eV): m/z (%) = 429 (M+, 33), 233 (70), 159 (100).
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO6: 430.2224; found:
Yield: 33.4 mg (51%); yellow oil; dr = 1.6:1.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.0 Hz, 1 H), 7.21–7.18 (m, 3
H), 6.91 (t, J = 8.0 Hz, 1 H), 6.85–6.80 (m, 3 H), 6.67 (t, J = 7.2 Hz, 1 H),
5.40–5.37 (m, 0.6 H), 5.34–5.32 (m, 0.4 H), 3.68 (s, 1.9 H), 3.67 (s, 1.2
H), 3.55 (s, 3 H), 2.79 (s, 1.2 H), 2.72 (s, 1.9 H), 2.53–2.45 (m, 1 H),
2.43–2.34 (m, 1 H), 2.02–1.89 (m, 1 H), 1.20 (t, J = 6.2 Hz, 3 H).
430.2237.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
G.-H. Pan et al.
Paper
Synthesis
Ethyl 4-(4-Methoxyphenyl)-4-[(4-methoxyphenyl)amino]-2,2-di-
methylbutanoate (4ada)
5-(3-Methoxyphenyl)-1-(4-methoxyphenyl)-3-methylpyrrolidin-
2-one (5baa)
Yield: 45.7 mg (64%); colorless oil.
Yield: 31.7 mg (51%); dr = 1.2:1.
1H NMR (400 MHz, CDCl3): δ = 7.20 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.4
Hz, 2 H), 6.65 (d, J = 8.8 Hz, 2 H), 6.39 (d, J = 9.6 Hz, 2 H), 4.36–4.32 (m,
1 H), 4.15–4.00 (m, 2 H), 3.76 (s, 3 H), 3.67 (s, 6 H), 2.29–2.23 (m, 1 H),
1.76–1.72 (m, 1 H), 1.25 (d, J = 18.4 Hz, 6 H), 1.20 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 178.4, 158.4, 151.7, 141.2, 136.7,
127.2, 114.7, 114.2, 113.9, 69.8, 60.7, 55.7, 55.2, 55.1, 49.3, 41.3, 28.1,
23.6, 14.1.
Isomer A
Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.8 Hz, 2 H), 7.22 (t, J = 8.0
Hz, 1 H), 6.80–6.74 (m, 4 H), 6.74 (s, 1 H), 5.10–5.07 (m, 1 H), 3.75 (s, 3
H), 3.73 (s, 3 H), 2.86–2.80 (m, 1 H), 2.25–2.21 (m, 2 H), 1.29 (d, J = 6.8
Hz, 3 H).
LRMS (EI, 70 eV): m/z (%) = 357 (M+, 13), 233 (49), 159 (100).
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO4: 358.2013; found:
13C NMR (100 MHz, CDCl3): δ = 176.9, 160.1, 156.5, 143.1, 131.8,
130.0, 123.0, 118.0, 113.9, 112.7, 111.6, 61.9, 55.3, 55.2, 37.7, 35.7,
16.0.
358.2018.
LRMS (EI, 70 eV): m/z (%) = 311 (M+, 100), 242 (18), 204 (20).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
2-Ethyl-4-(4-methoxyphenyl)-4-morpholinobutanenitrile (4aek)
Yield: 40.9 mg (71%); colorless oil; dr = 1.3:1.
312.1602.
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 7.6 Hz, 2 H), 7.09 (d, J = 7.6
Hz, 2 H), 6.90–6.87 (m, 4 H), 3.81 (s, 6 H), 3.67–3.61 (m, 9 H), 3.48–
3.42 (m, 1 H), 2.81–2.73 (m, 1 H), 2.42–2.06 (m, 11 H), 1.90–1.74 (m, 2
H), 1.71–1.55 (m, 4 H), 1.09 (t, J = 7.2 Hz, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.2, 159.1, 130.2, 129.6, 129.4,
128.7, 122.2, 121.9, 113.9, 113.5, 67.6, 67.2, 67.0, 66.1, 55.2, 51.0,
49.7, 35.0, 33.7, 30.7, 30.4, 25.9, 25.3, 11.5, 11.4.
Isomer B
Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 8.4 Hz, 2 H), 7.16 (t, J = 8.0
Hz, 1 H), 6.79–6.70 (m, 5 H), 5.07–5.03 (m, 1 H), 3.72 (s, 3 H), 3.71 (s, 3
H), 2.82–2.68 (m, 2 H), 1.65–1.60 (m, 1 H), 1.36 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.2, 159.8, 156.7, 143.0, 131.0,
129.7, 124.6, 118.9, 113.8, 112.7, 112.3, 62.1, 55.2, 55.1, 38.7, 37.4,
16.6.
LRMS (EI, 70 eV): m/z (%) = 288 (M+, 2), 206 (100), 134 (26), 121 (12).
HRMS (ESI): m/z [M + H]+ calcd for C17H25N2O2: 289.1911; found:
LRMS (EI, 70 eV): m/z (%) = 311 (M+, 100), 242 (13), 204 (25).
289.1925.
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
312.1599.
1,5-Bis(4-Methoxyphenyl)-3-methylpyrrolidin-2-one (5aaa)
The isomers of compounds 5aaa-5daa were separated by silica gel
column chromatography (hexane/ethyl acetate) and their correspon-
dent characterization is reported below.
1-(4-Methoxyphenyl)-3-methyl-5-(p-tolyl)pyrrolidin-2-one (5caa)
Yield: 35.4 mg (60%); dr = 1.2:1.
Yield: 14.3 mg (23%); dr = 1.2:1.
Isomer A
Isomer A
Yellow oil.
Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.8 Hz, 2 H), 7.13–7.07 (m, 4
H), 6.78 (d, J = 8.8 Hz, 2 H), 5.10–5.07 (m, 1 H), 3.72 (s, 3 H), 2.87–2.77
(m, 1 H), 2.30 (s, 3 H), 2.24–2.19 (m, 2 H), 1.29 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 156.4, 138.3, 137.7, 131.9,
129.6, 125.7, 123.1, 113.9, 61.7, 55.3, 37.9, 35.7, 21.0, 16.0.
LRMS (EI, 70 eV): m/z (%) = 295 (M+, 100), 226 (10), 145 (71).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO2: 296.1645; found:
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 8.0
Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H), 5.09–5.06 (m,
1 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 2.87–2.77 (m, 1 H), 2.23–2.18 (m, 2 H),
1.29 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.9, 158.8, 156.4, 133.1, 131.7,
126.9, 123.1, 114.1, 113.8, 61.4, 55.2, 55.1, 37.8, 35.7, 15.9.
LRMS (EI, 70 eV): m/z (%) = 311 (M+, 77), 161 (100), 147 (25).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
296.1653.
312.1603.
Isomer B
Yellow oil.
Isomer B
1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 8.8 Hz, 2 H), 7.08–7.03 (m, 4
H), 6.74 (d, J = 8.8 Hz, 2 H), 5.06–5.02 (m, 1 H), 3.70 (s, 3 H), 2.80–2.67
(m, 2 H), 2.26 (s, 3 H), 1.64–1.59 (m, 1 H), 1.36 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.2, 156.7, 138.2, 137.3, 131.0,
129.4, 126.5, 124.7, 113.7, 62.0, 55.2, 39.0, 37.5, 21.0, 16.6.
LRMS (EI, 70 eV): m/z (%) = 295 (M+, 100), 226 (13), 145 (74).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO2: 296.1645; found:
Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.16 (d, J = 8.4 Hz, 2 H), 7.09 (d, J = 8.4
Hz, 2 H), 6.76 (d, J = 8.0 Hz, 2 H), 6.73 (d, J = 8.8 Hz, 2 H), 5.03–5.00 (m,
1 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 2.78–2.66 (m, 2 H), 1.66–1.58 (m, 1 H),
1.35 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 158.8, 156.6, 132.9, 130.8,
127.8, 124.8, 113.9, 113.6, 61.7, 55.1 (2 C), 38.9, 37.3, 16.4.
296.1657.
LRMS (EI, 70 eV): m/z (%) = 311 (M+, 77), 161 (100), 147 (26).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
312.1601.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
G.-H. Pan et al.
Paper
Synthesis
1-(4-Methoxyphenyl)-3-methyl-5-phenylpyrrolidin-2-one (5daa)
13C NMR (100 MHz, CDCl3): δ = 176.5, 159.1, 132.4, 130.0, 127.4,
127.3, 114.0, 60.7, 60.1, 55.3, 44.3, 25.1, 14.2.
LRMS (EI, 70 eV): m/z (%) = 234 (M+, 23), 133 (100).
Yield: 30.9 mg (55%); dr = 1.2:1.
HRMS (ESI): m/z [M + H]+ calcd for C14H19O3: 235.1329; found:
Isomer A
Yellow oil.
235.1334.
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.4 Hz, 2 H), 7.31 (t, J = 7.6
Hz, 2 H), 7.25 (d, J = 7.2 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 2 H), 6.77 (d, J = 8.4
Hz, 2 H), 5.13–5.10 (m, 1 H), 3.72 (s, 3 H), 2.88–2.78 (m, 1 H), 2.26–
2.21 (m, 2 H), 1.30 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 177.0, 156.5, 141.3, 131.8, 128.9,
127.5, 125.8, 123.0, 113.9, 61.9, 55.3, 37.8, 35.6, 15.9.
Funding Information
We thank the Natural Science Foundation of China (Nos. 21472039,
21625203 and 21402046), the Jiangxi Province Science and Technolo-
gy Project (Nos. 20171BCB23055, 20171ACB21032, 20171ACB20015
and 20165BCB18007), and Technology Project of Jiangxi Provincial
LRMS (EI, 70 eV): m/z (%) = 281 (M+, 100), 204 (25), 149 (25).
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2: 282.1489; found:
Department of Education (GJJ160725) for financial support.
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Supporting Information
Isomer B
Yellow oil.
Supporting information for this article is available online at
1H NMR (400 MHz, CDCl3): δ = 7.26–7.17 (m, 7 H), 6.74 (d, J = 8.4 Hz, 2
H), 5.10–5.06 (m, 1 H), 3.69 (s, 3 H), 2.82–2.68 (m, 2 H), 1.68–1.60 (m,
1 H), 1.36 (d, J = 6.8 Hz, 3 H).
https://doi.org/10.1055/s-0036-1591903.
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References
13C NMR (100 MHz, CDCl3): δ = 177.1, 156.7, 141.2, 130.9, 128.7,
127.6, 126.6, 124.7, 113.7, 62.2, 55.2, 38.9, 37.4, 16.6.
LRMS (EI, 70 eV): m/z (%) = 281 (M+, 100), 204 (29), 149 (21).
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2: 282.1489; found:
282.1493.
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Methyl 3-(3,4-Dihydronaphthalen-1-yl)-2-methylpropanoate
(6ha)
Yield: 13.8 mg (30%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.18 (m, 2 H), 7.13 (d, J = 4.0 Hz, 2
H), 5.87 (t, J = 4.4 Hz, 1 H), 3.64 (s, 3 H), 2.97–2.91 (m, 1 H), 2.73–2.69
(m, 3 H), 2.44–2.39 (m, 1 H), 2.25–2.20 (m, 2 H), 1.15 (d, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 176.9, 136.8, 134.1, 133.8, 127.6,
127.1, 126.7, 126.3, 122.5, 51.5, 38.1, 37.0, 28.3, 23.1, 16.7.
LRMS (EI, 70 eV): m/z (%) = 230 (M+, 28), 171 (23), 143 (100).
HRMS (ESI): m/z [M + H]+ calcd for C15H19O2: 231.1380; found:
231.1385.
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Ethyl 2-Methyl-2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]propa-
noate (7)
Yield: 92.1 mg (85%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.20–4.14 (m, 2 H), 1.56 (t, J = 6 Hz, 2
H), 1.47 (s, 6 H), 1.33–1.25 (m, 7 H), 1.15 (s, 6 H), 1.00 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 177.5, 80.8, 60.3, 59.3, 40.4, 33.2, 24.2,
20.2, 16.8, 13.9.
LRMS (EI, 70 eV): m/z (%) = 271 (M+, 43), 156 (100).
HRMS (ESI): m/z [M + H]+ calcd for C15H30NO3: 272.2220; found:
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272.2225.
Ethyl 4-(4-Methoxyphenyl)-2,2-dimethylbut-3-enoate (8)
Yield: 38.4 mg (82%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8
Hz, 2 H), 6.37 (d, J = 16.4 Hz, 1 H), 6.25 (d, J = 16 Hz, 1 H), 4.17–4.11
(m, 2 H), 3.80 (s, 3 H), 1.39 (s, 6 H), 1.25 (t, J = 7.2 Hz, 3 H).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J