Metal-Free Insertion of Sulfoxonium Ylides into Arylamines in Water

Article abstract of DOI:10.1055/s-0040-1707186

Carbenoid-based N-H insertions have undergone significant development with respect to C-N bond formation in recent years. However, the existing methods suffer from unstable starting materials, expensive metal catalysts and organic solvents. Herein, insertion of sulfoxonium ylides into arylamines under metal-free conditions has been developed. The method employs water as solvent at mild temperature and is amenable to the late-stage modification of structurally complex bioactive compounds.

Full text of DOI:10.1055/s-0040-1707186

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–F
paper
A
en
H. He et al.
Paper
Synthesis
Metal-Free Insertion of Sulfoxonium Ylides into Arylamines
in Water
Hua Hea,b
R3
N
O
O
S
O
R3
R4
Kaichuan Yanb
Jianglian Lib
Ruizhi Laib
Yi Luob
Mei Guan*a
Yong Wu*b
H+
H
N
R1
R1
R4
H2O
R2
R2
• Metal-free
• Up to 87% yield
• 25 examples
• Water as solvent
• Suitable for late-stage modification
a West China Hospital, Sichuan University, Chengdu, 610041, P. R. of China
413046786@qq.com
b Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry and Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, No. 17 Southern Renmin Road, Chengdu,
Sichuan 610041, P. R. of China
wyong@scu.edu.cn
Received: 25.05.2020
Accepted after revision: 12.06.2020
Published online: 21.07.2020
um ylide derived carbenoids in 1993; Mangion then investi-
gated a more general methodology in 2009 (Scheme 1b).8
Although these methods offer generally better carbene pre-
cursors for N–H insertion reactions, they suffer from the
need for expensive metal catalysts and organic solvents.9 In
2016, Burtoloso described a catalyst-free insertion of sulf-
oxonium ylides into aryl thiols, but the authors did not as-
sess amine reactivity.10
To expand the applications of sulfoxonium ylides, here-
in, we describe a simple and metal-free N–H insertion reac-
tion of easily prepared sulfoxonium ylides and commercial-
ly available amines, through which -amino acid esters can
be obtained (Scheme 1c). Furthermore, because of the char-
acteristics of water as solvent and ambient reaction tem-
perature, this strategy is more suitable for chemical biology
than the metal–carbenoid N–H insertions.11 It is worth
mentioning that König and Metzger reported the reaction
of a similar -sulfoxonium acetate derivative with aniline in
DOI: 10.1055/s-0040-1707186; Art ID: ss-2020-g0285-op
Abstract Carbenoid-based N–H insertions have undergone significant
development with respect to C–N bond formation in recent years. How-
ever, the existing methods suffer from unstable starting materials, ex-
pensive metal catalysts and organic solvents. Herein, insertion of sulf-
oxonium ylides into arylamines under metal-free conditions has been
developed. The method employs water as solvent at mild temperature
and is amenable to the late-stage modification of structurally complex
bioactive compounds.
Key words sulfoxonium ylides, metal-free, N–H insertion, C–N forma-
tion, -amino acid ester
Nitrogen-containing compounds are extremely import-
ant because of their ubiquity in natural products and bioac-
tive molecules.1 For decades, organic chemists have studied
in depth the construction of C–N bonds. Metal-catalyzed C–
N cross-coupling reactions have been established as one of
the most general protocols.2 Carbenoid based N–H inser-
tions, on the other hand, have undergone significant devel-
opment with respect to C–N bond formation in recent
years. In these insertion reactions, metal–carbenoids de-
rived from diazo compounds are most widely used (Scheme
1a).3 However, diazo compounds are toxic, unstable, and
potentially explosive. It is thus highly desirable to develop
more suitable carbene precursors.4
Sulfonium and sulfoxonium ylides have been investigat-
ed as synthetic precursors in organic transformations since
they were first described in 1930.5 In addition to their ini-
tial applications in epoxidation, cyclopropanation, aziridi-
nation reactions, and [2,3]-sigmatropic or Stevens rear-
rangements,6 sulfoxonium ylides have recently gained
prominence as potentially safer surrogates of diazo com-
pounds in metal carbene reactions.7 Baldwin first reported
the rhodium-catalyzed N–H insertion reaction of sulfoxoni-
a) Diazo compound mediated N–H insertion reactions
R3
R3
O
O
O
H N
R4
MLn
– N2
N
N2
MLn
R1
R4
R1
R1
R2
R2
R2
b) Sulfoxonium ylide mediated N–H insertion reactions
R3
N
O
O
S
O
R3
R4
MLn
H
N
R1
R1
R4
– DMSO
R2
R2
c) Metal-free insertion of sulfoxonium ylides into amines (this work)
R3
N
O
O
S
R3
R4
O
H+
H
N
R1
R1
R4
H2O
R2
R2
• Metal-free • Water as solvent • Suitable for late-stage modification
Scheme 1 Related N–H insertion reactions
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. He et al.
Paper
Synthesis
the presence of HCl in 1965,12 but the only example in this
report required elevated temperature and gave a moderate
yield.
R3
Ar
O
R3
HN
Ar
S
N
HNO3 (50 mol%)
COOR2
COOR2
R1
R1
H2O
We initially studied reactions of sulfoxonium ylide 1a
with aniline 2a in dichloromethane (CH2Cl2) at 25 °C. Fortu-
nately, the ideal -amino acid ester 3a was obtained in 60%
yield (Table 1, entry 1). Subsequently, tetrahydrofuran
(THF), dichloroethane (DCE) and other organic solvents
were tested but their use failed to increase the yield (entries
2–5). However, the reaction proceeded well in water (entry
6). Considering that protonation of the ylide double bond is
conducive to the nucleophilic displacement of dimethyl
sulfoxide (DMSO),10 we tried different acids as additives,
and we found that nitric acid can effectively improve the
conversion of sulfoxonium ylide 1a (entries 7–11). We fur-
ther explored the temperature, reaction time, and the num-
ber of equivalents of 2a and nitric acid (for additional de-
tails see the Supporting Information), and finally estab-
lished the optimal conditions (entry 12).
35 °C 24 h
1
3
2
O
O
R
HN
HN
HN
COOEt
COOEt
COOEt
3n, 81%a
3m, 80%
Cl
3a, R = H, 81%
NO2
3b, R = 4-OMe, 83%
3c, R = 3-OMe, 75%
3d, R = 2-OMe, 62%
3e, R = 4-Me, 63%
3f, R = 3-Me, 80%
3g, R = 2-Me, 84%a
3h, R = 4-Cl, 54%
3i, R = 3-Cl, 87%
3j, R = 2-Cl, 74%a
3k, R = 3-F, 53%
3l, R = 4-Br, 67%
HN
HN
Cl
COOEt
COOEt
3o, 61%
3p, 0%
HN
HN
COOEt
After finding the optimal conditions to synthesize -
amino acid ester 3, we next evaluated the scope of the reac-
tion by employing structurally different sulfoxonium ylides
and amines. Anilines containing electron-donating or
-withdrawing substituents at different positions proceeded
smoothly (Scheme 2). Among them, methoxy-, methyl- and
chloro-substituted anilines afforded the corresponding -
amino acid esters 3b–j in moderate to good yields. We
COOEt
3q, 26%
3r, 25%
HN
N
N
COOEt
COOEt
COOEt
3s, 54%
3t, 47%
3u, 66%
O
O
S
Table 1 Optimization of the Reaction Conditionsa
HN
HN
Ph
O
COOEt
N
O
S
R
O
O
NH2
S
HN
additive
3v, R = 4-Cl, 67%
3w, R = 4-CN, 79%
3x, R = 4-Me, 84%
3y, 86%
COOEt
solvent
T (°C) 24 h
COOEt
no reaction
1a
2a
3a
Scheme 2 Scope of sulfoxonium ylides and amines. Reagents and con-
ditions: 1 (0.1 mmol), 2 (0.3 mmol), HNO3 (50 mol%), H2O (2 mL), 24 h,
35 °C under air. Isolated yields given. a Additive (2.0 equiv).
Entry
Additive
Solvent
T (°C)
Yield (%)b
1
2
−
CH2Cl2
THF
25
25
25
25
25
25
25
25
25
25
25
35
60
51
32
trace
26
62
65
41
72
63
39
81
−
found that ortho-substituted substrates exhibited lower
yields, possibly due to steric hindrance. Especially, 3g and 3j
were only obtained in good yields with higher equivalent of
HNO3. Bromine- and fluorine- substituted anilines gave
slightly lower yields when compared to chloro-substituted
aniline (3k–l). Considering the ubiquity of poly-substituted
aromatic amines, we further investigated some disubstitut-
ed aniline substrates and found that substrates with two
electron-donating substituents had little effect on the yield
(3m, 3n), but the substrate with two electron-withdrawing
substituents affected the yield of the reaction (3o). Surpris-
ingly, nitro-substituted substrates were not suitable for this
reaction (3p). When anilines were replaced with naphthyl-
amines, the corresponding products 3q and 3r were only
obtained in relatively low yields. In addition to aromatic
3
−
DCE
DMF
HOAc
H2O
H2O
H2O
H2O
H2O
H2O
H2O
4
−
5
−
6
−
7
HCOOH
1-AdCOOH
HNO3
HCl
8
9
10
11
12c
H2SO4
HNO3
a Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), additive (20 mol%),
solvent (2 mL) for 24 h at the specified temperature under air.
b Isolated yield.
c Additive (0.5 equiv).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

C
H. He et al.
Paper
Synthesis
primary amines, aromatic secondary amines could also be
amenable to the reaction (3s, 3t). Interestingly, the indole
substrate did not afford the desired -amino acid ester un-
der the optimal conditions; instead, it provided the 3-sub-
stituted product 3u. Aliphatic amines were not good candi-
dates for this reaction. Subsequently, sulfoxonium ylides
possessing different substituents were also investigated
(3v–y). Unfortunately, both -carbonyl sulfoxonium ylides
and imidoyl sulfoxonium ylide failed to undergo N–H inser-
tion reaction under these conditions. We speculate that the
electron-withdrawing group in the -position of sulfoxoni-
um ylide may increase its stability, but, on the other hand,
it may also reduce its reactivity. Donor–acceptor sulfoxoni-
um ylides have a suitable balance of stability and activity,
but the -carbonyl sulfoxonium ylide is too stable to react
in this reaction.
reaction, which proceeds at mild temperature, may open a
new window to constructing C–N bonds in the field of bio-
chemistry.
Unless noted, all reactions were carried out in flame-dried glassware
with magnetic stirring under an atmosphere of air. Solvents used
were of analytical purity. The product purification was done using sil-
ica gel column chromatography. NMR spectra were recorded with a
Varian spectrometer (400 MHz for 1H, 101 MHz for 13C and 376 MHz
for 19F). Chemical shifts are reported in  units (ppm) referenced to an
internal SiMe4 standard for 1HNMR and chloroform-d ( = 77.16 ppm)
for 13C NMR. HRMS spectra were recorded with a Waters Q-TOF Pre-
mier. Melting points were measured with YRT-3 melting point appa-
ratus (Shantou Keyi Instrument & Equipment Co., Ltd., Shantou, Chi-
na).
Compounds 3 and 5; General Procedure
To demonstrate the practical utility of the method as a
synthetic tool, a 10-fold scale-up of the reaction was con-
ducted and the yield was only slightly reduced (Scheme 3).
To a flame-dried reaction tube equipped with a magnetic stir bar was
added the sulfoxonium ylide 1 (0.1 mmol), aryl amine 2 (0.3 mmol)
and 68% HNO3 (0.05 mmol). Then H2O (2 mL) was added and the mix-
ture was stirred at 35 °C for 24 h. The solvent was then removed un-
der reduced pressure and the residue was purified by silica gel chro-
matography (EtOAc/petroleum ether, 1:20) to give pure product.
O
S
NH2
HN
standard conditions
+
COOEt
COOEt
Ethyl 2-Phenyl-2-(phenylamino)acetate (3a)
Yield: 81% (20.7 mg); light-yellow oil.
1a
1 mmol
2a
3a
77%
1H NMR (400 MHz, CDCl3):  = 7.52 (dt, J = 8.4, 2.0 Hz, 2 H), 7.40–7.30
(m, 3 H), 7.17–7.10 (m, 2 H), 6.71 (tt, J = 7.4, 1.2 Hz, 1 H), 6.60–6.56
(m, 2 H), 5.08 (s, 1 H), 4.32–4.09 (m, 2 H), 1.22 (t, J = 7.2 Hz, 3 H).
Scheme 3 10-fold scale-up reaction
13C NMR (100 MHz, CDCl3):  = 172.0, 146.1, 137.9, 129.4, 129.0,
128.4, 127.4, 118.2, 113.5, 62.0, 61.0, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NNaO2: 278.1151; found:
278.1158.
Notably, this metal-free approach could be used for late-
stage functionalization of structurally complex bioactive
compounds. For example, cholesterol-derived sulfoxonium
ylide 4 reacted with aniline 2a to afford the desired -ami-
no acid ester 5 in 41% yield (Scheme 4).
In summary, we have developed a N–H insertion of sulf-
oxonium ylides under metal-free conditions that affords the
corresponding -amino acid esters through C–N formation.
This strategy does not require unstable starting materials or
metal catalysts and is amenable to the late-stage modifica-
tion of structurally complex bioactive compounds. In con-
trast to the N–H insertions of metal–carbenoids that are
commonly used, we believe this water-mediated insertion
Ethyl 2-((4-Methoxyphenyl)amino)-2-phenylacetate (3b)
Yield: 83% (23.7 mg); light yellow solid; mp 84.9–86.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.50 (d, J = 7.2 Hz, 2 H), 7.34 (dt, J =
14.1, 7.2 Hz, 3 H), 6.73 (d, J = 8.9 Hz, 2 H), 6.54 (d, J = 8.9 Hz, 2 H), 5.01
(s, 1 H), 4.28–4.09 (m, 2 H), 3.71 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.2, 152.6, 140.4, 138.0, 128.9,
128.3, 127.4, 115.0, 114.9, 61.8, 61.8, 55.8, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO3: 308.1257; found:
308.1260
H
H
O
O
H
H
H
H
H
S
N
O
O
O
standard conditions
2a
4
5, 41%
Scheme 4 Late-stage modification of bioactive compounds
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

D
H. He et al.
Paper
Synthesis
Ethyl 2-((3-Methoxyphenyl)amino)-2-phenylacetate (3c)
1H NMR (400 MHz, CDCl3):  = 7.47 (d, J = 6.8 Hz, 2 H), 7.40–7.27 (m,
3 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.47 (d, J = 8.8 Hz, 2 H), 5.01 (s, 1 H),
4.31–4.07 (m, 2 H), 1.21 (t, J = 7.2 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 171.6, 144.6, 137.4, 129.2, 129.0,
128.5, 127.3, 122.8, 114.6, 62.1, 60.9, 14.2.
Yield: 75% (21.4 mg); light-yellow solid; mp 98.2–100.4 °C.
1H NMR (400 MHz, CDCl3):  = 7.50 (d, J = 7.0 Hz, 2 H), 7.34 (dt, J =
14.0, 7.0 Hz, 3 H), 7.03 (t, J = 8.2 Hz, 1 H), 6.27 (dd, J = 8.2, 2.4 Hz, 1 H),
6.19 (dd, J = 8.0, 2.4 Hz, 1 H), 6.12 (d, J = 2.4 Hz, 1 H), 5.06 (s, 1 H),
4.29–4.07 (m, 2 H), 3.71 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
HRMS (ESI) m/z [M + Na]+ calcd for C16H16ClNNaO2: 312.0762; found:
13C NMR (100 MHz, CDCl3):  = 171.9, 160.8, 147.5, 137.8, 130.1,
312.0765.
128.9, 128.3, 127.3, 106.5, 103.4, 99.6, 62.0, 60.9, 55.1, 14.2.
Ethyl 2-((3-Chlorophenyl)amino)-2-phenylacetate (3i)
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO3: 308.1257; found:
Yield: 87% (25.2 mg); light-yellow solid; mp 84.7–86.2 °C.
308.1261.
1H NMR (400 MHz, CDCl3):  = 7.48 (dd, J = 8.4, 1.6 Hz, 2 H), 7.40–7.29
(m, 3 H), 7.01 (t, J = 8.0 Hz, 1 H), 6.69–6.39 (m, 3 H), 5.03 (s, 1 H),
4.29–4.08 (m, 2 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.6, 147.2, 137.3, 135.1, 130.3,
129.1, 128.5, 127.3, 118.1, 113.3, 111.7, 62.1, 60.6, 14.2.
Ethyl 2-((2-Methoxyphenyl)amino)-2-phenylacetate (3d)
Yield: 62% (17.7 mg); light-yellow solid; mp 55.7–57.4 °C.
1H NMR (400 MHz, CDCl3):  = 7.53–7.49 (m, 2 H), 7.37–7.27 (m, 3 H),
6.78 (dd, J = 7.6, 1.6 Hz, 1 H), 6.73 (td, J = 7.6, 1.6 Hz, 1 H), 6.66 (td, J =
7.6, 1.6 Hz, 1 H), 6.36 (dd, J = 7.6, 1.6 Hz, 1 H), 5.06 (s, 1 H), 4.30–4.07
(m, 2 H), 3.89 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C16H16ClNNaO2: 312.0767; found:
312.0770.
13C NMR (100 MHz, CDCl3):  = 171.9, 147.2, 137.9, 136.1, 128.9,
128.3, 127.4, 121.2, 117.5, 110.8, 109.7, 61.8, 60.9, 55.6, 14.2.
Ethyl 2-((2-Chlorophenyl)amino)-2-phenylacetate (3j)
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO3: 308.1257; found:
Yield: 74% (21.4 mg); light-yellow solid; mp 59.5–62.6 °C.
1H NMR (400 MHz, CDCl3):  = 7.53–7.47 (m, 2 H), 7.41–7.27 (m, 4 H),
6.99 (ddd, J = 8.0, 7.6, 1.6 Hz, 1 H), 6.62 (td, J = 7.6, 1.6 Hz, 1 H), 6.38
(dd, J = 8.0, 1.6 Hz, 1 H), 5.69 (s, 1 H), 5.09 (s, 1 H), 4.35–4.06 (m, 2 H),
1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.3, 142.1, 137.3, 129.4, 129.0,
128.5, 127.8, 127.2, 119.8, 118.1, 112.2, 62.1, 60.7, 14.2.
308.1265.
Ethyl 2-Phenyl-2-(p-tolylamino)acetate (3e)
Yield: 63% (17.0 mg); light-yellow solid; mp 74.4–76.9 °C.
1H NMR (400 MHz, CDCl3):  = 7.50 (dd, J = 8.4, 1.2 Hz, 2 H), 7.38–7.27
(m, 3 H), 6.94 (d, J = 8.4 Hz, 2 H), 6.49 (d, J = 8.4 Hz, 2 H), 5.05 (s, 1 H),
4.28–4.09 (m, 2 H), 2.20 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C16H16ClNNaO2: 312.0767; found:
13C NMR (100 MHz, CDCl3):  = 172.1, 143.8, 138.0, 130.0, 128.9,
312.0762.
128.28, 127.4, 127.3, 113.7, 61.9, 61.2, 20.5, 14.2.
Ethyl 2-((3-Fluorophenyl)amino)-2-phenylacetate (3k)
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO2: 292.1308; found:
Yield: 53% (14.5 mg); light-yellow solid; mp 90.6–92.1 °C.
292.1311.
1H NMR (400 MHz, CDCl3):  = 7.48 (dt, J = 8.4, 2.2 Hz, 2 H), 7.40–7.29
(m, 3 H), 7.05 (td, J = 8.1, 6.6 Hz, 1 H), 6.42–6.32 (m, 2 H), 6.22 (dt, J =
11.4, 2.3 Hz, 1 H), 5.12 (s, 1 H), 5.02 (s, 1 H), 4.32–4.08 (m, 2 H), 1.22
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.6, 164.0 (d, JC–F = 243.1 Hz), 147.8
(d, JC–F = 10.8 Hz), 137.3, 130.4 (d, JC–F = 10.1 Hz), 129.0, 128.5, 127.3,
Ethyl 2-Phenyl-2-(m-tolylamino)acetate (3f)
Yield: 80% (21.5 mg); light-yellow solid; mp 108.4–110.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 7.2 Hz, 2 H), 7.34 (dt, J =
14.0, 7.2 Hz, 3 H), 7.01 (t, J = 7.6 Hz, 1 H), 6.53 (d, J = 7.6 Hz, 1 H), 6.43
(s, 1 H), 6.37 (d, J = 8.0 Hz, 1 H), 5.07 (s, 1 H), 4.89 (s, 1 H), 4.30–4.08
(m, 2 H), 2.24 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.0, 146.2, 139.1, 138.0, 129.2,
128.9, 128.3, 127.3, 119.2, 114.4, 110.5, 61.9, 60.9, 21.7, 14.2.
109.4 (d, JC–F = 2.4 Hz), 104.6 (d, JC–F = 21.5 Hz), 100.3 (d, JC–F
=
25.5 Hz), 62.1, 60.7, 14.2.
19F NMR (376 MHz, CDCl3):  = –112.72.
HRMS (ESI): m/z [M + Na]+ calcd for C16H16FNNaO2: 296.1057; found:
296.1061.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO2: 292.1308; found:
292.1317.
Ethyl 2-((4-Bromophenyl)amino)-2-phenylacetate (3l)
Ethyl 2-Phenyl-2-(o-tolylamino)acetate (3g)
Yield: 67% (22.4 mg); light-yellow oil.
Yield: 84% (22.6 mg); light-yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.49–7.44 (m, 2 H), 7.38–7.30 (m, 3 H),
7.19 (d, J = 8.8 Hz, 2 H), 6.43 (d, J = 8.8 Hz, 2 H), 5.01 (s, 1 H), 4.28–4.09
(m, 2 H), 1.21 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 7.2 Hz, 2 H), 7.33 (dt, J =
14.0, 7.2 Hz, 3 H), 7.07 (d, J = 7.2 Hz, 1 H), 6.97 (t, J = 7.6 Hz, 1 H), 6.64
(t, J = 7.2 Hz, 1 H), 6.34 (d, J = 8.0 Hz, 1 H), 5.10 (s, 1 H), 4.29–4.10 (m,
2 H), 2.28 (s, 3 H), 1.21 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.6, 145.0, 137.3, 132.1, 129.0,
13C NMR (100 MHz, CDCl3):  = 172.1, 144.2, 137.9, 130.3, 128.9,
128.5, 127.3, 115.1, 109.9, 62.1, 60.8, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H16BrNNaO2: 356.0257; found:
128.3, 127.3, 127.1, 122.6, 117.8, 110.8, 62.0, 60.9, 17.7, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO2: 292.1308; found:
356.0265.
292.1316.
Ethyl 2-(Benzo[d][1,3]dioxol-5-ylamino)-2-phenylacetate (3m)
Ethyl 2-((4-Chlorophenyl)amino)-2-phenylacetate (3h)
Yield: 80% (23.9 mg); brown oil.
Yield: 54% (15.6 mg); yellow solid; mp 87.9–89.2 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

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H. He et al.
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1H NMR (400 MHz, CDCl3):  = 7.48 (d, J = 7.2 Hz, 2 H), 7.34 (dt, J =
13.4, 7.2 Hz, 3 H), 6.59 (d, J = 8.3 Hz, 1 H), 6.21 (d, J = 2.2 Hz, 1 H), 5.99
(dd, J = 8.3, 2.2 Hz, 1 H), 5.85–5.77 (m, 2 H), 4.98 (s, 1 H), 4.28–4.08
(m, 2 H), 1.21 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.43–7.34 (m, 3 H), 7.34–7.27 (m, 4 H),
6.89 (d, J = 8.2 Hz, 2 H), 6.82 (t, J = 7.3 Hz, 1 H), 5.65 (s, 1 H), 4.35–4.21
(m, 2 H), 2.81 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.0, 150.0, 136.1, 129.4, 128.8,
128.6, 128.2, 118.1, 113.58, 65.9, 61.2, 34.7, 14.4.
13C NMR (100 MHz, CDCl3):  = 172.0, 148.4, 141.8, 140.1, 137.8,
128.9, 128.4, 127.3, 108.7, 105.3, 100.7, 96.7, 61.9, 61.76, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H17NNaO4: 322.1050; found:
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO2: 292.1308; found:
292.1315.
322.1051.
Ethyl 2-(Indolin-1-yl)-2-phenylacetate (3t)
Ethyl 2-((2,4-Dimethylphenyl)amino)-2-phenylacetate (3n)
Yield: 47% (13.2 mg); light-yellow oil.
Yield: 81% (23.0 mg); light-yellow solid; mp 90.6–92.6 °C.
1H NMR (400 MHz, CDCl3):  = 7.46–7.32 (m, 5 H), 7.13–6.99 (m, 2 H),
6.69 (t, J = 7.6 Hz, 1 H), 6.47 (d, J = 7.6 Hz, 1 H), 5.27 (s, 1 H), 4.34–4.15
(m, 2 H), 3.66 (q, J = 8.9 Hz, 1 H), 3.21–3.09 (m, 1 H), 3.02–2.84 (m,
2 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.4, 151.1, 135.4, 130.4, 128.80,
128.8, 128.4 127.2, 124.8, 118.4, 106.9, 64.0, 61.2, 50.0, 28.3, 14.4.
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 7.0 Hz, 2 H), 7.33 (dt, J =
14.4, 7.0 Hz, 3 H), 6.90 (s, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.26 (d, J =
8.1 Hz, 1 H), 5.08 (s, 1 H), 4.30–4.10 (m, 2 H), 2.26 (s, 3 H), 2.19 (s,
3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.2, 141.8, 138.1, 131.2, 128.9,
128.2, 127.3, 127.3, 126.9, 122.7, 111.0, 61.9, 61.1, 20.47, 17.6, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C12H21NNaO2: 308.1465; found:
HRMS (ESI): m/z [M + Na]+ calcd for C18H19NNaO2: 304.1308; found:
304.1310.
308.1466.
Ethyl 2-(1H-Indol-3-yl)-2-phenylacetate (3u)
Ethyl 2-((3,5-Dichlorophenyl)amino)-2-phenylacetate (3o)
Yield: 66% (18.4 mg); light-yellow oil.
Yield: 61% (19.8 mg); light-yellow solid; mp 116.8–119.2 °C.
1H NMR (400 MHz, CDCl3):  = 8.11 (s, 1 H), 7.49–7.40 (m, 3 H), 7.38–
7.27 (m, 4 H), 7.22–7.15 (m, 2 H), 7.07 (t, J = 7.6 Hz, 1 H), 5.25 (s, 1 H),
4.27–4.17 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 173.1, 138.8, 136.4, 128.6, 128.5,
127.3, 126.8, 123.3, 122.4, 119.8, 119.2, 114.0, 111.3, 61.3, 49.1, 14.3.
1H NMR (400 MHz, CDCl3):  = 7.45 (d, J = 6.8 Hz, 2 H), 7.36 (dt, J =
10.5, 6.8 Hz, 3 H), 6.66 (s, 1 H), 6.41 (d, J = 1.8 Hz, 2 H), 5.20 (brs, 1 H),
4.99 (s, 1 H), 4.29–4.08 (m, 2 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.2, 147.6, 136.7, 135.6, 129.2,
128.7, 127.2, 118.0, 111.7, 62.3, 60.4, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H15Cl2NNaO2: 346.0372;
HRMS (ESI): m/z [M + Na]+ calcd for C18H17NNaO2: 302.1151; found:
302.1154.
found: 346.0371.
Ethyl 2-(4-Chlorophenyl)-2-(phenylamino)acetate (3v)
Ethyl 2-(Naphthalen-2-ylamino)-2-phenylacetate (3q)
Yield: 67% (19.4 mg); colorless oil.
Yield: 26% (7.9 mg); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.45 (d, J = 8.4 Hz, 2 H), 7.32 (d, J =
8.4 Hz, 2 H), 7.12 (t, J = 7.9 Hz, 2 H), 6.71 (t, J = 7.3 Hz, 1 H), 6.53 (d, J =
7.6 Hz, 2 H), 5.03 (s, 1 H), 4.27–4.11 (m, 2 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.4, 145.8, 136.5, 134.2, 129.4,
129.1, 128.7, 118.4, 113.5, 62.2, 60.3, 14.2.
1H NMR (400 MHz, CDCl3):  = 7.64 (t, J = 8.2 Hz, 2 H), 7.58–7.49 (m,
3 H), 7.41–7.28 (m, 4 H), 7.18 (t, J = 7.5 Hz, 1 H), 6.97 (dd, J = 8.8,
2.4 Hz, 1 H), 6.66 (s, 1 H), 5.21 (s, 1 H), 4.33–4.11 (m, 2 H), 1.24 (t, J =
7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.9, 143.7, 137.5, 135.0, 129.2,
129.0, 128.4, 127.8, 127.7, 127.3, 126.4, 126.1, 122.4, 118.1, 105.8,
62.0, 60.9, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H16ClNNaO2: 312.0762; found:
312.0770.
HRMS (ESI): m/z [M + Na]+ calcd for C20H19NNaO2: 328.1308; found:
328.1312.
Ethyl 2-(4-Cyanophenyl)-2-(phenylamino)acetate (3w)
Yield: 79% (22.9 mg); light-yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.65 (s, 3 H), 7.16–7.08 (m, 2 H), 6.80–
6.65 (m, 2 H), 6.50 (d, J = 7.9 Hz, 2 H), 5.11 (s, 1 H), 4.29–4.12 (m, 2 H),
1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.5, 145.4, 143.5, 132.7, 129.5,
128.1, 118.6, 115.2, 113.5, 112.3, 62.6, 60.6, 14.11.
Ethyl 2-(Naphthalen-1-ylamino)-2-phenylacetate (3r)
Yield: 25% (7.6 mg); brown oil.
1H NMR (400 MHz, CDCl3):  = 8.06–8.00 (m, 1 H), 7.82–7.76 (m, 1 H),
7.58 (d, J = 6.7 Hz, 2 H), 7.57–7.43 (m, 2 H), 7.35 (dt, J = 12.3, 6.7 Hz,
3 H), 7.24–7.16 (m, 2 H), 6.34 (dd, J = 6.9, 1.6 Hz, 1 H), 5.24 (s, 1 H),
4.34–4.14 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.0, 141.2, 137.6, 134.4, 129.0,
128.8, 128.4, 127.3, 126.5, 126.0, 125.1, 123.6, 120.2, 118.1, 105.7,
62.1, 61.0, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H16N2NaO2: 303.1104; found:
303.1102.
Ethyl 2-(Phenylamino)-2-(p-tolyl)acetate (3x)
Yield: 84% (22.6 mg); light-yellow oil.
HRMS (ESI): m/z [M + Na]+ calcd for C20H19NNaO2: 328.1308; found:
328.1310.
1H NMR (400 MHz, CDCl3):  = 7.38 (d, J = 7.9 Hz, 2 H), 7.19–7.07 (m,
4 H), 6.69 (t, J = 7.3 Hz, 1 H), 6.57 (d, J = 7.9 Hz, 2 H), 5.03 (s, 1 H),
4.29–4.08 (m, 2 H), 2.34 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.1, 146.2, 138.1, 134.8, 129.6,
129.3, 127.2, 118.1, 113.5, 61.9, 60.6, 21.3, 14.2.
Ethyl 2-(Methyl(phenyl)amino)-2-phenylacetate (3s)
Yield: 54% (14.5 mg); light-yellow oil.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

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H. He et al.
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Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO2: 292.1308; found:
292.1311.
(2) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
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Isobutyl 2-Phenyl-2-(phenylamino)acetate (3y)
Yield: 86% (24.4 mg); white solid; mp 73.9–76.3 °C.
1H NMR (400 MHz, CDCl3):  = 7.51 (d, J = 6.9 Hz, 2 H), 7.33 (dt, J =
15.0, 7.0 Hz, 3 H), 7.12 (t, J = 7.8 Hz, 2 H), 6.69 (t, J = 7.3 Hz, 1 H), 6.57
(d, J = 7.9 Hz, 2 H), 5.08 (s, 1 H), 3.96–3.87 (m, 2 H), 1.86 (dq, J = 13.3,
6.8 Hz, 1 H), 0.81 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3):  = 172.0, 146.1, 138.0, 129.3, 128.9,
128.3, 127.3, 118.1, 113.5, 71.8, 60.9, 27.8, 18.9, 18.9.
HRMS (ESI): m/z [M + Na]+ calcd for C18H21NNaO2: 306.1465; found:
306.1463.
Cholesteryl 2-Phenyl-2-(phenylamino)acetate (5)
(4) (a) Jia, M.; Ma, S. Angew. Chem. Int. Ed. 2016, 55, 9134. (b) Xia,
Y.; Wang, J. Chem. Soc. Rev. 2017, 46, 2306.
Yield: 41% (24.4 mg); light-yellow solid; mp 148.2–151.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.50 (d, J = 7.4 Hz, 2 H), 7.33 (dt, J =
14.5, 7.6 Hz, 3 H), 7.12 (t, J = 7.7 Hz, 2 H), 6.69 (t, J = 7.3 Hz, 1 H), 6.56
(d, J = 7.9 Hz, 2 H), 5.33 (dd, J = 37.9, 5.1 Hz, 1 H), 5.04 (s, 1 H), 4.94 (s,
1 H), 4.64 (tt, J = 11.4, 5.1 Hz, 1 H), 2.36 (d, J = 8.1 Hz, 1 H), 2.18–1.78
(m, 6 H), 1.62–1.32 (m, 12 H), 1.25–1.01 (m, 9 H), 0.99 (s, 3 H), 0.91
(d, J = 6.1 Hz, 3 H), 0.89–0.84 (m, 6 H), 0.67 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 171.4, 146.2, 139.4, 139.3, 137.9,
137.9, 129.4, 128.9, 128.9, 128.3, 127.3, 123.2, 123.0, 118.1, 113.5,
75.6, 61.0, 56.8, 56.3, 50.1, 42.4, 39.8, 39.7, 38.2, 37.0, 36.7, 36.3, 35.9,
32.0, 32.0, 28.4, 28.2, 27.9, 24.4, 24.0, 23.0, 22.7, 21.2, 19.5, 18.9, 12.0.
(5) Ingold, C. K.; Jessop, J. A. J. Chem. Soc. 1930, 713.
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Chem. Rev. 2019, 119, 8701. (d) Lu, L.-Q.; Li, T.-R.; Wang, Q.;
Xiao, W.-J. Chem. Soc. Rev. 2017, 46, 4135. (e) Xia, X.-D.; Lu, L.-
Q.; Liu, W.-Q.; Chen, D.-Z.; Zheng, Y.-H.; Wu, L.-Z.; Xiao, W.-J.
Chem. Eur. J. 2016, 22, 8432.
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B.; Dias, R. M. P.; Leonarczyk, I. A. Eur. J. Org. Chem. 2013, 5005.
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(b) Mangion, I. K.; Nwamba, I. K.; Shevlin, M.; Huffman, M. A.
Org. Lett. 2009, 11, 3566.
HRMS (ESI): m/z [M + Na]+ calcd for C41H57NNaO2: 618.4282; found:
618.4284.
(9) (a) Mangion, I. K.; Ruck, R. T.; Rivera, N.; Huffman, M. A.;
Shevlin, M. Org. Lett. 2011, 13, 5480. (b) Mangion, I. K.; Weisel,
M. Tetrahedron Lett. 2010, 51, 5490. (c) Phelps, A. M.; Chan, V. S.;
Napolitano, J. G.; Krabbe, S. W.; Schomaker, J. M.; Shekhar, S.
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Funding Information
This work was supported by the National Natural Science Foundation
of China (grant numbers 81573286 and 81373259).
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(11) (a) Ball, Z. T. Acc. Chem. Res. 2013, 46, 560. (b) Chen, Z.; Popp, B.
V.; Bovet, C. L.; Ball, Z. T. ACS Chem. Biol. 2011, 6, 920. (c) Chen,
Z.; Vohidov, F.; Coughlin, J. M.; Stagg, L. J.; Arold, S. T. J. Am.
Chem. Soc. 2012, 134, 10138. (d) Antos, J. M.; McFarland, J. M.;
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Angew. Chem. Int. Ed. 2012, 51, 12000.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707186.
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References
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F