TfOH-Catalyzed N-H Insertion of α-Substituted-α-Diazoesters with Anilines Provides Access to Unnatural α-Amino Esters

Article abstract of DOI:10.1021/acs.joc.0c02588

A time-economical TfOH-catalyzed N-H insertion between anilines and α-alkyl and α-aryl-α-diazoacetates provides a straightforward approach to access unnatural α-amino esters, which readily undergo various transformations and can thus be used for the synthesis of pharmaceutically relevant molecules. The α-amino esters were obtained in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.0c02588

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Article
TfOH-Catalyzed N−H Insertion of α‑Substituted-α-Diazoesters with
Anilines Provides Access to Unnatural α‑Amino Esters
Sha Hu, Jiale Wu, Zuolin Lu, Jiaqi Wang, Yuan Tao, Meifen Jiang,* and Fener Chen*
Cite This: J. Org. Chem. 2021, 86, 3223−3231
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ABSTRACT: A time-economical TfOH-catalyzed N−H insertion
between anilines and α-alkyl and α-aryl-α-diazoacetates provides a
straightforward approach to access unnatural α-amino esters, which
readily undergo various transformations and can thus be used for the
synthesis of pharmaceutically relevant molecules. The α-amino esters
were obtained in moderate to excellent yields.
To date, various methods have been developed to access
INTRODUCTION
■
Unnatural α-amino esters are an essential structural motif in
many pharmaceutically relevant and nucleic acid-labeling
compounds and have also been employed as synthetically
attractive intermediates for the synthesis of biologically active
molecules in pharmaceutical chemistry.1 Representative
examples are illustrated in Figure 1, such as cholesteryl ester
unnatural α-amino derivatives (Scheme 1). The selected
Scheme 1. Strategies to Access Unnatural α-Amino Esters
Figure 1. Selected biologically active unnatural α-amino derivatives.
transfer protein inhibitor (I),2 nucleic acid-labeling agent (II),3
N-phenylphenylglycine (III),4 human corticotropin-releasing
factor antagonist, and potent transient receptor potential
melastatin 8 antagonist (IV).5 The medicinal importance of
unnatural α-amino esters and their derivatives has aroused
great interest from the scientific community for developing
new and improved synthetic methods, which have tremen-
dously advanced the development of the unnatural α-amino
acid-containing drugs and nucleic acid-labeling compounds.
Received: October 30, 2020
Published: December 30, 2020
https://dx.doi.org/10.1021/acs.joc.0c02588
© 2020 American Chemical Society
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a
existing approaches toward such privilege structures involve:
(i) N-alkylation of anilines with α-bromophenylesters;6 (ii)
transfer hydrogenation of imino esters with Hantzsch
Table 1. Optimization of Reaction conditions
b
entry Bro
̷
nsted acid catalyst (mol %)
solvent
time (h) yield (%)
dihydropyridine by Co-phosphoric acid or7 Bronsted acid8
̷
1
2
3
4
5
6
7
8
MsOH (20)
TsOH (20)
TFA (20)
H2SO4 (20)
HCl (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
TfOH (20)
none
DCM
DCM
DCM
DCM
DCM
DCM
DCE
MeCN
acetone
dioxane
Et2O
1
2
1
68
72
75
72
74
80
75
60
56
50
52
50
75
NR
40
25
95
and carboxyl-tailed benzothiazoline using a trifluoroacetic acid
(TFA) catalyst;9 (iii) amination of aryl azides with methyl
phenylacetates by Ru(TPP)CO or Ru(TPP)(py)2;10 (iv)
oxidative dehydrogenative cross-coupling of N-arylglycine
esters with phenols by transition-metal catalysts (Cu, Rh, or
Ru),11 N-substituted anilines under CuCl,12 and α-alkylation
of N-arylglycine esters with diacyl peroxides,13 respectively; (v)
reductive coupling of alkyl and arylglyoxylate esters with
anilines using Cu/BINAP14 or HFIP15 as a catalyst; (vi) N−H
insertion of sulfoxonium ylides with anilines in the presence of
0.5
0.5
0.17
0.17
0.17
0.17
0.17
0.17
0.17
0.17
2
9
10
11
12
13
14
15
16
17
16
a catalytic amount of [Ir(COD)Cl]2 or AuCl(SMe2);17 (vii)
THF
AcOEt
DCM
DCM
DCM
DCM
phosphoric acid-catalyzed C−N bond formation of sulfonium
ylide esters with p-methoxyphenyl;18 (viii) urea-catalyzed N−
H insertion−arylation of α-nitrodiazoesters with anilines;19
and (ix) N−H insertion of α-aryl-α-diazoacetates with anilines
by transition-metal catalysts (Cu,20 Rh,21 Ru,22 Pd,23 Ir,24 or
Fe25). Despite notable progress in this area, however, among
all of these methods, the use of air-sensitive metal reagents or
transition-metal catalysts, harsh reaction conditions, and
functional group incompatibility all have limitations; con-
sequently, the development of a general methodology for the
synthesis of unnatural α-amino esters without the use of metal
reagents or transition-metal catalysts using diazo chemistry
under mild reaction conditions presents a fundamental and
practical challenge yet not resolved. Moreover, chemists often
consider several economic factors such as the atom economy,
step economy, and pot economy.26 Herein, we reported the
time-economical TfOH-catalyzed N−H insertion of anilines
with α-alkyl and α-aryl-α-diazoacetates. This strategy provides
rapid access to unnatural α-amino esters, displaying excellent
functional group tolerance and high chemo-regioselectivity
under mild conditions.
c
TfOH (10)
TfOH (5)
TfOH (30)
12
12
0.17
a
Reaction conditions: methyl α-phenyl-α-diazoacetate 1a (0.2 mmol,
1.0 equiv), p-toluidine 2a (0.24 mmol, 1.2 equiv), and catalyst (mol
%) in the solvent (0.8 mL, 0.25 M) at 50 °C under air. Complete
b
c
conversion reaction time of 1a. NR: no reaction.
the reaction became much slower (entries 15 and 16). To our
delight, increasing the TfOH loading to 30 mol % had a
significant effect on the outcome, affording a 95% yield of the
desired product 3aa (entry 17).
With the optimal reaction conditions, further studies focused
on evaluating the scope of anilines (Scheme 2). A variety of
anilines bearing both electron-donating groups, such as Me, Et,
isopropyl, tert-butyl, MeO, and electron-withdrawing groups,
such as F and Cl at any position of the phenyl rings, could be
smoothly converted into the corresponding products (3ab−
3am) in high to excellent yields. Satisfactorily, a nonsubstituted
aniline was also compatible with this transformation to give α-
amino ester 3an in 72% yield. Furthermore, meta-, meta-
dimethylaniline and meta-, meta-, para-trimethylaniline were
subjected to the optimal reaction conditions, furnishing the
desired products 3ao−3ap in high yields. In addition to
anilines, the secondary amines N-methyl-substituted anilines,
regardless of the position and nature of the substituents, were
well tolerated, affording the desired insertion products 3aq−
3av in high yields. However, the ortho-, ortho-disubstituted
aniline only offered 3aw in 38% yield. Benzylamine and tert-
butylamine did not give the desired products 3ax and 3ay.
Subsequently, some other methyl α-aryl and α-alkyl-α-
diazoacetates were prepared and investigated (Scheme 3). In
the beginning, the phenyl rings of α-diazoacetates attached
with different electron groups, including electron-donating and
electron-withdrawing groups, all worked well, providing the
desired insertion products 3ba−3na in 71−85% yields. To our
delight, α-alkyl-α-diazoacetate substrates were also effectively
reacted with p-toluidine (2a), and the desired products 3oa
and 3pa were obtained in 68 and 70% yields, respectively.
The synthetic utility of the reaction has been demonstrated
by the synthesis of IV, a potent transient receptor potential
melastatin 8 antagonist (Scheme 4). The TfOH-catalyzed N−
H insertion of methyl 2-diazo-2-(4-(trifluoromethyl)phenyl)-
acetate (1e) with 2-fluoroaniline (2l) under the optimized
conditions furnished the corresponding α-amino ester (3el)
with an 85% yield. Hydrolysis of 3el under the base conditions
RESULTS AND DISCUSSION
Initial experiments began by screening a series of Bro
■
̷
nsted
acids for their ability to catalyze the insertion between α-
phenyl-α-diazoacetate (1a) and p-toluidine (2a) as model
(Table 1) substrates under reaction conditions similar to those
of our recently developed conditions for the cascade C−H
activation/lactonization of phenols and α-aryl-α-diazoesters.27
When 20 mol % of methanesulfonic acid (MsOH) was used as
the catalyst, the N−H insertion proceeded smoothly to give
the desired α-amino ester 3aa in 68% yield (entry 1). Other
Bro̷nsted acids, such as TsOH, TFA, H2SO4, and HCl as the
catalyst, gave comparable yield to MsOH (72−75%, entries 2−
5). Switching from TFA and MsOH to more acidic triflic acid
(TfOH) increased the yield of 3aa to 80% (entry 6). However,
significantly, the reaction time was dramatically shortened to
only 0.17 h. The screening continued concerning the reaction
solvent. Changing dichloromethane (DCM) to either 1,2-
dichloroethane (DCE), MeCN, acetone, dioxane, Et2O, THF,
or AcOEt all led to a decrease in the isolated yields (entries 7−
13). Control experiments show that no reaction occurred in
the absence of TfOH (entry 14). These results indicated that
the acidity of the Bro̷nsted acids strongly affected their
catalytic performance. By applying TfOH as the catalyst,
further optimization was conducted. Reducing the loading of
TfOH from 20 to 10 or 5 mol % resulted in a remarkable drop
in the product yield from 80 to 40 and 25%, respectively, and
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a
Scheme 2. Scope of Aniline Substrates
Scheme 3. Scope of α-Phenyl and α-Alkyldiazoacetate
Substrates
a
a
Reaction conditions: α-diazoacetates 1 (0.2 mmol, 1.0 equiv), p-
toluidine 2a (0.24 mmol, 1.2 equiv), and TfOH (0.06 mmol) in DCM
(0.8 mL, 0.25 M) at 50 °C for 0.17 h under air.
Scheme 4. Synthesis Utility of the Reaction
a
Reaction conditions: methyl α-aryl-α-diazoacetate 1a (0.2 mmol, 1.0
equiv), anilines 2 (0.24 mmol, 1.2 equiv), and TfOH (0.06 mmol) in
DCM (0.8 mL, 0.25 M) at 50 °C for 0.17 h under air.
(LiOH, H2O/MeOH) followed by amide bond formation with
phenylpyrrolidine gave the final product IV.5
To demonstrate the practicality and scalability of the
protocol, a larger-scale reaction was carried out under the
standard conditions in our study (Scheme 5).
Scheme 5. Larger-Scale Reaction
Based on our previous study and literature precedence,28,27
we propose a plausible mechanism (Scheme 6). The reaction
likely goes through the initial formation of a diazonium ion
intermediate A, which is generated from α-phenyl-α-diazo-
acetate (1a) in the presence of the TfOH catalyst. Then, the
diazonium ion A, undergoing a nucleophilic attack by p-
toluidine (2a), leads to the formation of the desired product α-
amino ester 3aa after the intermolecular N−H insertion
extrudes N2.
The overall process is atom-efficient, step-economic, and
highly functional group-tolerant. Further applications of this
methodology for synthesizing related bioactive natural
products are currently ongoing in our laboratory.
In conclusion, we have developed a time-economical TfOH-
catalyzed N−H insertion reaction of anilines with α-alkyl and
α-aryl-α-diazoacetates to provide rapid access to α-aryl
benzofuranones under mild reaction conditions in high yields.
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MHz, CDCl3) δ 7.49 (d, J = 7.1 Hz, 2H), 7.42−7.26 (m, 3H), 7.01 (t,
J = 7.8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.42 (s, 1H), 6.35 (d, J =
7.9 Hz, 1H), 5.08 (d, J = 5.5 Hz, 1H), 4.88 (d, J = 4.8 Hz, 1H), 3.73
(s, 3H), 2.23 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.4,
146.0, 139.0, 137.7, 129.1, 128.8, 128.3, 127.2, 119.1, 114.3, 110.3,
60.7, 52.8, 21.6. HRMS (ESI) m/z calcd for C16H18NO2, [M + H]+
256.1332; found: 256.1331. IR (neat) ν 3410, 3042, 3026, 2959,
2919, 2849, 1728, 1607, 1588, 1509, 1455, 1438, 1324, 1257, 1195,
1168, 773, 727, 697 cm−1. This is known.31
Scheme 6. Proposed Reaction Mechanism
Methyl 2-phenyl-2-(o-tolylamino)acetate (3ac). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3ac;
yellow oil (48.5 mg, yield 95%); 1H NMR (400 MHz, CDCl3) δ 7.49
(d, J = 7.1 Hz, 2H), 7.39−7.29 (m, 3H), 6.94 (d, J = 8.2 Hz, 2H),
6.49 (d, J = 8.4 Hz, 2H), 5.06 (s, 1H), 4.82 (s, 1H), 3.73 (s, 3H), 2.20
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.4, 143.6, 137.7,
129.7, 128.8, 128.2, 127.3, 127.2, 113.5, 61.0, 52.8, 20.4. HRMS (ESI)
m/z calcd for C16H17NNaO2, [M + Na]+ 278.1151; found: 278.1153.
IR (neat) ν 3426, 3061, 3030, 2952, 1739, 1607, 1587, 1513, 1454,
1316, 1212, 751 cm−1. This is known.31
Methyl 2-((4-ethylphenyl)amino)-2-phenylacetate (3ad). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3ad; yellow oil (47.3 mg, yield 88%); 1H NMR (400
MHz, CDCl3) δ 7.49 (d, J = 7.1 Hz, 2H), 7.40−7.27 (m, 3H), 6.96
(d, J = 8.1 Hz, 2H), 6.50 (d, J = 8.2 Hz, 2H), 5.05 (s, 1H), 4.84 (s,
1H), 3.73 (s, 3H), 2.50 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H).
13C {1H} NMR (100 MHz, CDCl3) δ 172.5, 143.9, 137.8, 133.9,
128.8, 128.5, 128.2, 127.2, 113.4, 61.0, 52.8, 27.9, 15.8. HRMS (ESI)
m/z calcd for C17H19NNaO2, [M + Na]+ 292.1308; found: 292.1305.
IR (neat) ν 3399, 3182, 3029, 2959, 2919, 2848, 1732, 1615, 1520,
1455, 1433, 1324, 1300, 1255, 1180, 827, 812, 728 cm−1. This is
known.32
EXPERIMENTAL SECTION
■
General Method. All reactions were carried out in a Schlenk tube
and a round flask. Column chromatography was performed over a
1
silica gel (200−300 mesh). H nuclear magnetic resonance (NMR)
spectra were recorded using a Bruker AM400 spectrometer; chemical
shifts (in ppm) were referred to CDCl3 (δ = 7.26 ppm). The 13C
NMR spectrum was obtained using the same NMR spectrometer and
was calibrated with CDCl3 (δ = 77.0 ppm). The following
abbreviations are used to illuminate the diversities: δ = chemical
shifts, J = coupling constant, s = singlet, d = doublet, t = triplet, q =
quartet, and m = multiplet. High-resolution mass spectrometry
(HRMS) was performed using a Bruker micrOTOF spectrometer
(ESI). DCE and DCM were purified by distillation with CaH2. The
heat source is an oil bath. All materials were obtained from
commercial suppliers unless otherwise stated, and most of the starting
materials were purchased from Adamas, Bide, and JiuDing. PE =
petroleum ether and EA = ethyl acetate.
Methyl 2-((4-isopropylphenyl)amino)-2-phenylacetate (3ae).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3ae; white solid (50.4 mg, yield 89%), mp 63−64 °C; H
NMR (400 MHz, CDCl3) δ 7.53−7.48 (m, 2H), 7.41−7.28 (m, 3H),
7.00 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.5 Hz, 2H), 5.05 (s, 1H), 4.84
(s, 1H), 3.73 (s, 3H), 2.83−2.70 (m, 1H), 1.19−1.15 (m, 6H). 13C
{1H} NMR (100 MHz, CDCl3) δ 172.5, 144.0, 138.6, 137.9, 128.8,
128.2, 127.3, 127.1, 113.4, 61.1, 52.7, 33.1, 24.1. HRMS (ESI) m/z
calcd HRMS (ESI+) calcd for C18H21NNaO2, [M + Na]+ 306.1464;
found: 306.1459. IR (neat) ν 3399, 3028, 2962, 2882, 1732, 1614,
1519, 1493, 1358, 1324, 1251, 1179, 742, 698 cm−1.
The typical procedure for the α-aryl-α-diazoesters is known.29
All of the compounds α-aryl-α-diazoacetates 1 are known and data
are consistent with the literature.30
Typical Procedure for the α-Aryl-α-Amino Esters 3. To the
mixture of α-aryl-α-diazoacetates 1 (0.2 mmol, 1.0 equiv) in DCM
(0.8 mL, 0.25 M) at 50 °C, TfOH (30 mol %) was added via a syringe
pump followed by the addition of anilines (0.24 mmol, 1.2 equiv)
quickly. After the completion of addition, the reaction was stirred for
0.17 h. After filtration, the solvent was removed under a reduced
pressure. The crude product was purified by flash chromatography on
a silica gel to afford the corresponding products 3.
Preparation of 3aa on a Larger Scale. To the mixture of α-
phenyl-α-diazoacetate 1a (2 mmol, 1.0 equiv) in DCM (0.8 mL, 0.25
M) at 50 °C, TfOH (30 mol %) was added via a syringe pump
followed by the addition of p-toluidine 2a (2.4 mmol, 1.2 equiv)
quickly. After the completion of addition, the reaction was stirred for
0.17 h. After filtration, the solvent was removed under a reduced
pressure. The crude product was purified by flash chromatography on
a silica gel (eluent/petroleum ether/EtOAc = 10:1) to afford 0.23 g of
3aa (yield 45%).
Methyl 2-((4-(tert-butyl)phenyl)amino)-2-phenylacetate (3af).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3af; yellow solid (54.6 mg, yield 92%), mp 113−114 °C; 1H
NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.1 Hz, 2H), 7.39−7.27 (m,
3H), 7.16 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 8.7 Hz, 2H), 5.05 (d, J =
5.3 Hz, 1H), 4.86 (d, J = 5.0 Hz, 1H), 3.73 (s, 3H), 1.24 (s, 9H). 13C
{1H} NMR (100 MHz, CDCl3) δ 172.5, 143.7, 140.9, 137.9, 130.3,
128.8, 128.2, 127.5, 127.3, 126.0, 113.1, 61.1, 52.7, 33.8, 31.5. HRMS
(ESI) m/z calcd for C19H24NO2, [M + H]+ 298.1802; found:
298.1804. IR (neat) ν 3421, 3391, 3029, 2954, 2918, 2866, 1737,
1614, 1520, 1493, 1451, 1435, 1320, 1260, 1208, 1195, 1178, 820,
735, 695 cm−1. This is known.33
Methyl 2-((4-methoxyphenyl)amino)-2-phenylacetate (3ag).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3ag; yellow solid (40.1 mg, yield 74%), mp 69−70 °C; H
Methyl 2-phenyl-2-(p-tolylamino)acetate (3aa). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3aa;
orange solid (48.5 mg, yield 95%), mp 107−108 °C; H NMR (400
NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.1 Hz, 2H), 7.42−7.27 (m,
3H), 6.82−6.77 (m, 1H), 6.76−6.71 (m, 1H), 6.70−6.63 (m, 1H),
6.38−6.32 (m, 1H), 5.48 (d, J = 5.4 Hz, 1H), 5.09 (d, J = 5.9 Hz,
1H), 3.89 (s, 3H), 3.74 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
172.3, 147.0, 137.7, 135.9, 128.8, 128.2, 127.2, 1201.0, 117.4, 110.6,
109.5, 60.7, 55.4, 52.7. HRMS (ESI) m/z calcd for C16H17NNaO3,
[M + Na]+ 294.1101; found: 294.1092. IR (neat) ν 3430, 3061, 3029,
2960, 2836, 1737, 1602, 1519, 1508, 1454, 1329, 1258, 1247, 1219,
1143, 1104, 1022, 790, 734, 697 cm−1. This is known.20h
1
MHz, CDCl3) δ 7.49 (d, J = 7.1 Hz, 2H), 7.39−7.28 (m, 3H), 6.94
(d, J = 8.1 Hz, 2H), 6.49 (d, J = 8.3 Hz, 2H), 5.07 (d, J = 5.0 Hz, 1H),
4.82 (s, 1H), 3.73 (s, 3H), 2.20 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.4, 143.6, 137.7, 129.7, 128.8, 128.2, 127.3, 127.2, 113.5,
61.0, 52.7, 20.4. HRMS (ESI) m/z calcd for C16H18NO2, [M + H]+
256.1338; found 256.1331. IR (neat) ν 3407, 3038, 3005, 2949, 2915,
2844, 1739, 1619, 1523, 1492, 1455, 1434, 1317, 1298, 1256, 1208,
1176, 805, 725, 698 cm−1. This is known.20h
Methyl 2-((3-methoxyphenyl)amino)-2-phenylacetate (3ah).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
Methyl 2-phenyl-2-(m-tolylamino)acetate (3ab). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3ab;
yellow solid (47.9 mg, yield 94%), mp 100−101 °C; H NMR (400
1
afforded 3ah; yellow liquid (39.0 mg, yield 72%); H NMR (400
1
MHz, CDCl3) δ 7.52−7.46 (m, 2H), 7.39−7.29 (m, 3H), 7.03 (t, J =
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8.1 Hz, 1H), 6.27 (dd, J = 7.5, 2.3 Hz, 1H), 6.18 (dd, J = 8.4, 1.8 Hz,
1H), 6.10 (t, J = 2.2 Hz, 1H), 5.07 (d, J = 5.8 Hz, 1H), 4.98 (d, J = 5.5
Hz, 1H), 3.72 (d, J = 10.2 Hz, 6H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.2, 160.6, 147.2, 137.5, 123.0, 128.9, 128.3, 127.2, 106.4,
103.3, 99.5, 60.7, 55.0, 52.8. HRMS (ESI) m/z calcd for
C16H17NNaO3, [M + Na]+ 294.1101; found: 294.1097. IR (neat) ν
3401, 3006, 2951, 2936, 1733, 1592, 1508, 1456, 1425, 1336, 1210,
1194, 812, 771, 700 cm−1. This is known.25a
2950, 2919, 2848, 1727, 1632, 1603, 1502, 1470, 1433, 1321, 1258,
1193, 827, 737 cm−1. This is known.20h
Methyl 2-phenyl-2-(phenylamino)acetate (3an). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3an;
1
yellow solid (34.7 mg, yield 72%), mp 75−76 °C; H NMR (400
MHz, CDCl3) δ 7.50 (d, J = 7.3 Hz, 2H), 7.41−7.27 (m, 3H), 7.13 (t,
J = 7.7 Hz, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 8.0 Hz, 2H),
5.08 (s, 1H), 4.96 (s, 1H), 3.74 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.3, 145.9, 137.6, 129.2, 128.9, 128.3, 127.2, 118.1, 113.4,
60.7, 52.8. HRMS (ESI) m/z calcd for C15H15NNaO2, [M + Na]+
264.0995; found: 264.0993. IR (neat) ν 3401, 3028, 2952, 2920,
2848, 1731, 1604, 1505, 1454, 1429, 1329, 1254, 1216, 1177, 1138,
747, 737, 693 cm−1. This is known.25a
Methyl 2-((2-methoxyphenyl)amino)-2-phenylacetate (3ai). Pu-
rification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3ai; yellow solid (40.7 mg, yield 75%), mp 69−70 °C; H
NMR (400 MHz, CDCl3) δ 7.54−7.49 (m, 2H), 7.39−7.29 (m, 3H),
6.82−6.77 (m, 1H), 6.76−6.71 (m, 1H), 6.71−6.61 (m, 1H), 6.40−
6.32 (m, 1H), 5.48 (d, 1H), 5.09 (d, J = 5.2 Hz, 1H), 3.89 (s, 3H),
3.74 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.3, 147.0,
137.7, 135.9, 128.8, 128.2, 127.2, 121.0, 117.4, 110.6, 109.5, 60.7,
55.4, 52.7. HRMS (ESI) m/z calcd for C16H17NNaO3, [M + Na]+
294.1101; found: 294.1100. IR (neat) ν 3429, 3061, 3029, 2958,
2919, 1737, 1601, 1519, 1454, 1329, 1220, 1181, 1142, 1022, 733,
697 cm−1. This is known.25a
Methyl 2-((3,5-dimethylphenyl)amino)-2-phenylacetate (3ao).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3ao; white solid (46.3 mg, yield 86%), mp 145−146 °C; 1H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 2H), 7.39−7.29 (m,
3H), 6.37 (s, 1H), 6.21 (s, 2H), 5.07 (d, J = 5.7 Hz, 1H), 4.81 (d, J =
4.9 Hz, 1H), 3.74−3.68 (m, 3H), 2.18 (s, 6H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.5, 146.0, 138.9, 137.8, 128.8, 128.2, 127.2, 120.2,
111.3, 60.7, 52.8, 21.5. HRMS (ESI) m/z calcd for C17H20NO2, [M +
H]+ 270.1489; found: 270.1488. IR (neat) ν 3413, 3026, 2956, 2914,
2849, 1728, 1605, 1511, 1453, 1440, 1348, 1324, 1256, 1215, 1199,
1179, 1025, 823, 735, 691 cm−1.
Methyl 2-((4-fluorophenyl)amino)-2-phenylacetate (3aj). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3aj; yellow solid (41.4 mg, yield 80%), mp 76−77 °C; H
NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.1 Hz, 2H), 7.39−7.29 (m,
3H), 6.83 (t, J = 8.7 Hz, 2H), 6.52−6.45 (m, 2H), 5.02 (d, J = 4.0 Hz,
1H), 4.83 (d, J = 28.2 Hz, 1H), 3.73 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.2, 156.1 (C−F, 1JC−F = 235.8 Hz), 142.2 (C−
F, 4JC−F = 1.9 Hz), 137.3, 129.4, 128.9, 128.4, 127.2, 115.7 (C−F,
2JC−F = 22.4 Hz), 114.2 (C−F, 3JC−F = 7.5 Hz), 61.2, 52.8. HRMS
(ESI) m/z calcd for C15H15FNO2, [M + H]+ 260.1087; found:
260.1094. IR (neat) ν 3401, 3027, 2956, 2918, 1728, 1515, 1454,
1432, 1324, 1248, 1206, 1186, 821, 798, 771, 697 cm−1. This is
known.32
Methyl 2-phenyl-2-((3,4,5-trimethylphenyl)amino)acetate (3ap).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3ap; yellow liquid (45.3 mg, yield 80%); H NMR (400
MHz, CDCl3) δ 7.41 (d, J = 6.7 Hz, 2H), 7.37−7.30 (m, 3H), 6.76 (s,
2H), 4.88 (s, 1H), 4.28 (s, 1H), 3.68 (s, 3H), 2.21 (d, 9H). 13C {1H}
NMR (100 MHz, CDCl3) δ 173.9, 141.6, 138.6, 131.2, 129.6, 129.0,
128.6, 128.0, 127.0, 64.1, 52.4, 20.5, 18.8. HRMS (ESI) m/z calcd for
C18H22NO2, [M + H]+ 284.1645; found: 284.1648. IR (neat) ν 3375,
3028, 2950, 2917, 2855, 1739, 1485, 1453, 1435, 1206, 1169, 727,
697 cm−1.
Methyl 2-((3-fluorophenyl)amino)-2-phenylacetate (3ak). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3ak; yellow solid (44.0 mg, yield 85%), mp 108−109 °C;
1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 2H), 7.42−7.28
(m, 3H), 7.05 (q, J = 7.6 Hz, 1H), 6.37 (dd, J = 20.0, 8.8 Hz, 2H),
6.22 (d, J = 11.4 Hz, 1H), 5.12 (d, 1H), 5.04 (d, J = 5.5 Hz, 1H), 3.74
(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.9, 163.8 (C−F,
1JC−F = 243.1 Hz), 147.6 (C−F, 3JC−F = 10.7 Hz), 137.0, 130.3
(C−F, 3JC−F = 10.2 Hz), 129.0, 128.5, 127.2, 109.2 (C−F, 4JC−F =
2.2 Hz), 104.5 (C−F, 2JC−F = 21.5 Hz), 100.2 (C−F, 2JC−F = 25.5
Hz), 60.5, 52.9. HRMS (ESI) m/z calcd for C15H15FNO2, [M + H]+
260.1081; found: 260.1083. IR (neat) ν 3399, 3070, 3030, 2956,
2918, 2849, 1728, 1622, 1586, 1509, 1495, 1454, 1332, 1253, 1218,
1195, 1153, 823, 731, 699 cm−1. This is known.31
Methyl 2-(methyl(p-tolyl)amino)-2-phenylacetate (3aq). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3aq; yellow liquid (38.2 mg, yield 71%); H NMR (400
MHz, CDCl3) δ 7.36 (p, J = 6.7 Hz, 3H), 7.28 (d, J = 7.1 Hz, 2H),
7.08 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 5.61 (s, 1H), 3.77
(s, 3H), 2.76 (s, 3H), 2.28 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.4, 147.8, 135.9, 129.8, 128.6, 128.4, 128.0, 127.5, 113.9,
66.2, 51.9, 34.7, 20.3. HRMS (ESI) m/z calcd for C17H20NO2, [M +
H]+ 270.1489; found: 270.1487. IR (neat) ν 3359, 3029, 2919, 2849,
1747, 1617, 1519, 1369, 1304, 1197, 1108, 807, 729 cm−1.
Methyl 2-((4-methoxyphenyl)(methyl)amino)-2-phenylacetate
(3ar). Purification by column chromatography (EtOAc/hexane, 1:10
v/v) afforded 3ar; yellow liquid (43.3 mg, yield 76%); 1H NMR (400
MHz, CDCl3) δ 7.46−7.26 (m, 5H), 6.93−6.78 (m, 4H), 5.47 (s,
1H), 3.76 (d, J = 10.1 Hz, 6H), 2.74 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.4, 152.9, 144.5, 135.9, 128.6, 128.5, 128.1, 116.6,
114.6, 67.6, 55.6, 51.9, 35.6. HRMS (ESI) m/z calcd for
C17H19NNaO3, [M + Na]+ 308.1257; found: 308.1256. IR (neat) ν
3390, 2954, 2915, 2848, 1738, 1643, 1512, 1470, 1451, 1247, 1181,
1107, 1038, 872, 817, 721 cm−1.
Methyl 2-((4-fluorophenyl)(methyl)amino)-2-phenylacetate
(3as). Purification by column chromatography (EtOAc/hexane,
1:10 v/v) afforded 3as; yellow liquid (42.6 mg, yield 78%); 1H
NMR (400 MHz, CDCl3) δ 7.40−7.33 (m, 3H), 7.27 (dd, J = 9.6, 3.2
Hz, 2H), 7.01−6.92 (m, 2H), 6.85−6.77 (m, 2H), 5.52 (s, 1H), 3.77
(s, 3H), 2.75 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.2,
156.3 (C−H, 1JC−F = 237.3 Hz), 146.5 (C−F, 4JC−F = 1.9 Hz),
135.6, 128.7, 128.4, 128.2, 115.6 (C−F, 2JC−F = 18.5 Hz), 115.5
(C−F, 3JC−F = 3.8 Hz), 66.9, 52.0, 35.2. HRMS (ESI) m/z calcd for
C16H17FNO2, [M + H]+ 274.1238; found: 274.1232. IR (neat) ν
3359, 3183, 2957, 2919, 2849, 1745, 1658, 1632, 1510, 1470, 1428,
1262, 1107, 818, 725, 704 cm−1.
Methyl 2-((2-fluorophenyl)amino)-2-phenylacetate (3al). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3al; yellow oil (44.0 mg, yield 85%); H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.43−7.29 (m, 3H), 7.04−6.91
(m, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.63 (q, J = 6.5 Hz, 1H), 6.43 (t, J =
8.0 Hz, 1H), 5.21 (s, 1H), 5.09 (d, J = 6.0 Hz, 1H), 3.75 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 171.8, 151.6 (C−F, 1JC−F = 239.3
Hz), 137.1, 134.4 (C−F, 2JC−F = 11.7 Hz), 130.3, 128.9, 128.5,
127.2, 124.4 (C−F, 3JC−F = 3.6 Hz), 117.6 (C−F, 3JC−F = 7.0 Hz),
114.6 (C−F, 2JC−F = 18.4 Hz), 112.9 (C−H, 4JC−F = 3.0 Hz),
60.4, 52.9. HRMS (ESI) m/z calcd for C15H14FNNaO2, [M + Na]+
282.0901; found: 282.0897. IR (neat) ν 3420, 3069, 2954, 2918,
2848, 1741, 1621, 1515, 1455, 1332, 1256, 1216, 1177, 799, 744, 698
cm−1. This is known.32
Methyl 2-((4-chlorophenyl)amino)-2-phenylacetate (3am). Puri-
fication by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3am; yellow solid (43.5 mg, yield 79%), mp 77−78 °C;
1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 6.9 Hz, 2H), 7.38−7.30
(m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 5.03 (d, J
= 5.5 Hz, 1H), 5.00 (d, J = 5.9 Hz, 1H), 3.73 (s, 3H). 13C {1H} NMR
(100 MHz, CDCl3) δ 172.0, 144.4, 137.1, 129.1, 128.9, 128.5, 127.2,
122.7, 114.5, 60.7, 52.9. HRMS (ESI) m/z calcd for C15H15ClNO2,
[M + H]+ 276.0786; found: 276.0787. IR (neat) ν 3405, 3357, 3181,
Methyl 2-((4-chlorophenyl)(methyl)amino)-2-phenylacetate
(3at). Purification by column chromatography (EtOAc/hexane, 1:10
v/v) afforded 3at; yellow liquid (42.8 mg, yield 74%); 1H NMR (400
MHz, CDCl3) δ 7.36 (t, J = 7.3 Hz, 3H), 7.29−7.24 (m, 2H), 7.21 (d,
3227
https://dx.doi.org/10.1021/acs.joc.0c02588
J. Org. Chem. 2021, 86, 3223−3231

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
J = 8.7 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 5.60 (s, 1H), 3.78 (s, 3H),
2.76 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.0, 148.5,
135.4, 129.1, 128.7, 128.4, 128.3, 127.5, 123.0, 114.7, 66.0, 52.1, 34.6.
HRMS (ESI) m/z calcd for C16H17ClNO2, [M + H]+ 290.0942;
found: 290.0943. IR (neat) ν 3363, 3179, 3065, 2956, 2922, 1747,
1600, 1498, 1435, 1371, 1308, 1275, 1201, 1173, 1109, 1005, 811,
745, 700 cm−1.
Methyl 2-((4-bromophenyl)(methyl)amino)-2-phenylacetate
(3au). Purification by column chromatography (EtOAc/hexane,
1:10 v/v) afforded 3au; yellow liquid (46.6 mg, yield 70%);1H
NMR (400 MHz, CDCl3) δ 7.41−7.35 (m, 3H), 7.35 (d, J = 2.3 Hz,
1H), 7.33 (d, J = 2.3 Hz, 1H), 7.28−7.22 (m, 2H), 6.76−6.71 (m,
2H), 5.60 (s, 1H), 3.79 (s, 3H), 2.76 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.0, 148.8, 135.3, 131.9, 130.3, 128.7, 128.4, 128.3,
127.5, 115.1, 110.1, 65.8, 52.1, 34.6. HRMS (ESI) m/z calcd for
C16H15BrNO2, [M − H]− 332.0292; found: 332.0297. IR (neat) ν
3371, 2955, 2915, 2849, 1738, 1590, 1495, 1471, 1377, 1262, 1198,
1107, 809, 742, 698 cm−1.
3H), 2.34 (s, 3H), 2.20 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
172.6, 143.8, 138.6, 137.6, 129.7, 129.1, 128.7, 127.8, 127.3, 124.4,
113.5, 61.0, 5.72, 21.5, 20.4. HRMS (ESI) m/z calcd for C17H20NO2,
[M + H]+ 270.1489; found: 270.1491. IR (neat) ν 3360, 3028, 2952,
2921, 2862, 1731, 1688, 1659, 1589, 1519, 1455, 1406, 1278, 1236,
1150, 1037, 815, 770 cm−1.
Methyl 2-(p-tolylamino)-2-(4-(trifluoromethyl)phenyl)acetate
(3ea). Purification by column chromatography (EtOAc/hexane,
1
1:10 v/v) afforded 3ea; white oil (54.3 mg, yield 84%); H NMR
(400 MHz, CDCl3) δ 7.63 (q, J = 8.5 Hz, 4H), 7.09 (d, J = 7.2 Hz,
1H), 6.96 (t, J = 7.6 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 6.24−6.19 (m,
1H), 5.17 (d, J = 4.9 Hz, 1H), 5.01 (d, J = 4.6 Hz, 1H), 3.76 (s, 3H),
2.31 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.6, 143.4,
141.8, 130.3, 127.6, 127.0, 125.8 (C−F, 3JC−F = 3.8 Hz), 123.9 (C−
F, 1JC−F = 274.7 Hz), 122.6, 118.0, 110.6, 60.3, 53.2, 17.5.HRMS
(ESI) m/z calcd for C17H17F3NO2, [M + H]+ 324.1206; found:
324.1207. IR (neat) ν 3421, 3047, 2956, 2920, 2850, 1746, 1621,
1515, 1449, 1325, 1170, 1128, 1067, 749 cm−1.
Methyl 2-(4-(tert-butyl)phenyl)-2-(p-tolylamino)acetate (3fa).
Methyl 2-((2-fluorophenyl)(methyl)amino)-2-phenylacetate
(3av). Purification by column chromatography (EtOAc/hexane,
1:10 v/v) afforded 3av; yellow liquid (38.2 mg, yield 70%); 1H
NMR (400 MHz, CDCl3) δ 7.36 (d, J = 5.2 Hz, 5H), 7.09−7.00 (m,
3H), 6.99−6.88 (m, 1H), 5.41 (s, 1H), 3.72 (s, 3H), 2.74 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 172.0, 155.8 (C−F, 1JC−F = 244.8
Hz), 139.2 (C−F, 2JC−F = 12.0 Hz), 135.7, 130.3, 128.7, 128.5,
128.1, 127.5, 124.3 (C−F, 3JC−F = 3.5 Hz), 122.5 (C−F, 3JC−F =
8.0 Hz), 121.5 (C−F, 4JC−F = 3.0 Hz), 116.2 (C−F, 2JC−F = 20.9
Hz), 68.4 (C−F, 4JC−F = 6.1 Hz), 51.8, 35.6. HRMS (ESI) m/z
calcd for C16H16FNNaO2, [M + Na]+ 296.1057; found: 296.1056. IR
(neat) ν 3348, 2955, 2915, 2849, 1733, 1471, 1377, 1260, 1216, 1198,
1182, 1098, 802 cm−1.
Methyl 2-((2-ethyl-6-methylphenyl)amino)-2-phenylacetate
(3aw). Purification by column chromatography (EtOAc/hexane,
1:10 v/v) afforded 3aw; colorless oil (21.5 mg, yield 38%); 1H
NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 7.1 Hz, 2H), 7.34 (dt, J =
14.5, 7.0 Hz, 3H), 6.93 (dd, J = 13.4, 7.5 Hz, 2H), 6.78 (t, J = 7.4 Hz,
1H), 4.85 (d, J = 10.2 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 3.60 (s,
3H), 2.57 (q, J = 6.9 Hz, 2H), 2.18 (s, 3H), 1.09 (t, J = 7.4 Hz, 3H).
13C {1H} NMR (100 MHz, DMSO) δ 173.8, 144.0, 139.0, 135.3,
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3fa; brown oil (46.0 mg, yield 74%); H NMR (400 MHz,
CDCl3) δ 7.37 (q, J = 8.5 Hz, 4H), 6.93 (d, J = 8.1 Hz, 2H), 6.49 (d, J
= 8.3 Hz, 2H), 5.03 (d, J = 5.4 Hz, 1H), 4.72 (d, J = 4.7 Hz, 1H), 3.71
(s, 3H), 2.19 (s, 3H), 1.29 (s, 9H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.7, 151.2, 143.9, 134.6, 129.8, 128.9, 127.3, 126.9, 125.9,
125.6, 113.5, 60.8, 52.7, 34.6, 31.4, 20.4. HRMS (ESI) m/z calcd for
C20H26NO2, [M + H]+ 312.1958; found: 312.1953. IR (neat) ν 3405,
3028, 2959, 2924, 2867, 1740, 1619, 1521, 1414, 1316, 1297, 1266,
1175, 809 cm−1.
Methyl 2-([1,1′-biphenyl]-4-yl)-2-(p-tolylamino)acetate (3ga).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3ga; white solid (47.0 mg, yield 71%), mp 123−124 °C; 1H
NMR (400 MHz, CDCl3) δ 7.57 (d, J = 5.5 Hz, 6H), 7.43 (t, J = 7.5
Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 6.52 (d, J
= 8.3 Hz, 2H), 5.11 (d, J = 5.6 Hz, 1H), 4.85 (d, J = 5.3 Hz, 1H), 3.76
(s, 3H), 2.21 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 172.4,
143.6, 141.2, 140.5, 136.7, 129.8, 128.8, 127.6, 127.6, 127.4, 127.4,
127.1, 113.5, 60.7, 52.8, 20.4. HRMS (ESI) m/z calcd for C22H22NO2,
[M + H]+ 332.1645; found: 332.1647. IR (neat) ν 3407, 3069, 3000,
2909, 2848, 1738, 1615, 1519, 1483, 1436, 1321, 1174, 783, 768
cm−1.
129.8, 129.1, 129.0, 128.4, 127.5, 126.9, 122.4, 64.3, 52.8, 24.1, 19.3,
15.0. HRMS (ESI) m/z calcd for C18H22NO2, [M + H]+ 284.1645;
found: 284.1644. IR (neat) ν 3386, 3063, 2964, 2872, 1740, 1593,
1494, 1467, 1263, 1209, 1171, 778, 702 cm−1.
Methyl 2-(4-methoxyphenyl)-2-(p-tolylamino)acetate (3ha). Pu-
rification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
Methyl 2-(p-tolyl)-2-(p-tolylamino)acetate (3ba). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3ba;
yellow oil (42.0 mg, yield 78%); 1H NMR (400 MHz, CDCl3) δ 7.37
(d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 8.1 Hz, 2H),
6.48 (d, J = 8.3 Hz, 2H), 5.03 (d, J = 5.6 Hz, 1H), 4.76 (d, J = 3.0 Hz,
1H), 3.72 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.6, 143.7, 138.0, 134.7, 129.7, 129.5, 127.2, 127.1,
113.5, 60.7, 52.7, 21.1, 20.4. HRMS (ESI) m/z calcd for
C17H19NNaO2, [M + Na]+ 292.1308; found: 292.1308. IR (neat) ν
3360, 3022, 2953, 2919, 2853, 1732, 1615, 1519, 1435, 1306, 1261,
1192, 1172, 1134, 818, 803, 752 cm−1. This is known.34
afforded 3ha; brown solid (48.5 mg, yield 85%), mp 60−61 °C; H
NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.1
Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 8.3 Hz, 2H), 5.02 (s,
1H), 4.76 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 2.21 (s, 3H). 13C {1H}
NMR (100 MHz, CDCl3) δ 172.7, 159.5, 143.7, 129.7, 128.3, 127.2,
119.6, 114.2, 113.5, 60.3, 55.2, 52.6, 20.3. HRMS (ESI) m/z calcd for
C17H19NNaO3, [M + Na]+ 308.1257; found: 308.1248. IR (neat) ν
3356, 3003, 2956, 2917, 2836, 1728, 1613, 1515, 1452, 1248, 1168,
1035, 824, 808, 704 cm−1. This is known.20h
Methyl 2-(3-methoxyphenyl)-2-(p-tolylamino)acetate (3ia). Pu-
rification by column chromatography (EtOAc/hexane, 1:10 v/v)
1
Methyl 2-(m-tolyl)-2-(p-tolylamino)acetate (3ca). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3ca;
afforded 3ia; yellow solid (46.2 mg, yield 81%), mp 61−62 °C; H
NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 7.6
Hz, 1H), 7.03 (s, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.86−6.79 (m, 1H),
6.48 (d, J = 8.3 Hz, 2H), 5.01 (d, J = 4.6 Hz, 1H), 4.79 (s, 1H), 3.78
(s, 3H), 3.72 (s, 3H), 2.19 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3) δ 172.3, 159.9, 143.7, 139.3, 129.8, 129.7, 127.3, 119.6, 113.7,
113.5, 112.8, 61.0, 55.2, 52.7, 20.4. HRMS (ESI) m/z calcd for
C17H19NNaO3, [M + Na]+ 308.1257; found: 308.1258. IR (neat) ν
3398, 3006, 2952, 2917, 2868, 1729, 1619, 1607, 1526, 1485, 1429,
1306, 1263, 1246, 1156, 821, 767 cm−1.
1
yellow liquid (43.0 mg, yield 80%); H NMR (400 MHz, CDCl3) δ
7.39 (d, J = 7.0 Hz, 1H), 7.20 (d, J = 9.0 Hz, 3H), 6.94 (d, J = 8.1 Hz,
2H), 6.46 (d, J = 8.3 Hz, 2H), 5.26 (s, 1H), 4.66 (s, 1H), 3.72 (s,
3H), 2.53 (s, 3H), 2.20 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
172.9, 143.9, 136.6, 136.0, 130.9, 129.8, 128.1, 127.3, 126.6, 126.4,
113.3, 57.6, 52.6, 20.4, 19.5. HRMS (ESI) m/z calcd for
C17H19NNaO2, [M + Na]+ 292.1308; found: 292.1307. IR (neat) ν
3406, 3022, 2952, 2917, 2862, 1732, 1619, 1521, 1434, 1310, 1261,
1209, 1170, 801, 764, 738 cm−1.
Methyl 2-(3-fluorophenyl)-2-(p-tolylamino)acetate (3ja). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
Methyl 2-(o-tolyl)-2-(p-tolylamino)acetate (3da). Purification by
column chromatography (EtOAc/hexane, 1:10 v/v) afforded 3da;
1
afforded 3ja; yellow solid (43.7 mg, yield 80%), mp 66−67 °C; H
1
yellow liquid (39.8 mg, yield 74%); H NMR (400 MHz, CDCl3) δ
NMR (400 MHz, CDCl3) δ 7.25 (d, J = 27.9 Hz, 3H), 7.03−6.89 (m,
3H), 6.46 (d, J = 6.4 Hz, 2H), 5.04 (s, 1H), 4.84 (s, 1H), 3.74 (s,
3H), 2.20 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.8, 163.1
7.31−7.22 (m, 3H), 7.11 (d, J = 7.1 Hz, 1H), 6.94 (d, J = 8.0 Hz,
2H), 6.49 (d, J = 8.2 Hz, 2H), 5.00 (s, 1H), 4.76 (s, 1H), 3.72 (s,
3228
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Article
(C−F, 1JC−F = 247.1 Hz), 140.5 (C−F, 3JC−F = 6.2 Hz), 130.3
(C−F, 3JC−F = 8.0 Hz), 143.3, 129.8, 127.6, 122.9 (C−F, 4JC−F =
1.0 Hz), 115.2 (C−F, 2JC−F = 21.5 Hz), 114.2 (C−F, 2JC−F = 22.2
Hz), 113.5, 60.6, 52.9, 20.4. HRMS (ESI) m/z calcd for
C16H16FNNaO2, [M + Na]+ 296.1057; found: 296.1056. IR (neat)
ν 3401, 3061, 3021, 2949, 2919, 2847, 1732, 1611, 1590, 1523, 1484,
1449, 1436, 1304, 1256, 1206, 940, 805, 786, 773 cm−1.
222.1491. IR (neat) ν 3376, 2956, 2923, 2852, 1732, 1618, 1520,
1463, 1377, 1296, 1260, 1185, 1083, 1030, 808 cm−1.
Methyl 2-((2-fluorophenyl)amino)-2-(4-(trifluoromethyl)phenyl)-
acetate (3el). Purification by column chromatography (EtOAc/
hexane, 1:10 v/v) afforded 3el; yellow liquid (55.6 mg, yield 85%);
1H NMR (400 MHz, CDCl3) δ 7.63 (s, 4H), 7.00 (dd, J = 11.6, 8.1
Hz, 1H), 6.85 (t, J = 7.7 Hz, 1H), 6.65 (q, J = 7.6 Hz, 1H), 6.33 (t, J =
8.3 Hz, 1H), 5.32 (s, 1H), 5.15 (d, J = 5.5 Hz, 1H), 3.77 (s, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 170.9, 151.6 (C−J, 1JC−F = 239.7
Hz), 141.3, 133.9 (C−F, 3JC−F = 11.7 Hz), 130.7 (C−F, 2JC−F =
32.3 Hz), 127.6, 125.9 (C−F, 3JC−F = 3.7 Hz), 124.5 (C−F, 3JC−F
= 3.6 Hz) 124.5 (C−F, 3JC−F = 3.6 Hz), 123.9 (C−F, 1JC−F =
272.2 Hz), 118.0 (C−F, 3JC−F = 7.0 Hz), 114.8 (C−F, 2JC−F =
18.3 Hz), 112.8 (C−J, 4JC−F = 2.9 Hz), 60.1, 53.2. HRMS (ESI) m/
z calcd for C16H12F4NO2, [M − H]− 326.0810; found: 326.0794. IR
(neat) ν 3416, 3006, 2960, 2852, 1742, 1699, 1687, 1618, 1520, 1439,
1418, 1325, 1249, 1160, 1114, 1071, 844, 825, 745 cm−1. This is
known.5
Methyl 2-(4-chlorophenyl)-2-(p-tolylamino)acetate (3ka). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
1
afforded 3ka; brown solid (47.4 mg, yield 82%), mp 65−66 °C; H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.8
Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 6.44 (d, J = 7.8 Hz, 2H), 5.02 (d,
1H), 4.84 (s, 1H), 3.73 (s, 3H), 2.20 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 171.9, 143.3, 136.3, 134.1, 129.8, 129.0, 128.6, 127.5,
113.5, 60.3, 52.9, 20.4. HRMS (ESI) m/z calcd for C16H17ClNO2, [M
+ H]+ 290.0942; found: 290.0939. IR (neat) ν 3360, 3021, 2956,
2916, 2848, 1736, 1615, 1519, 1488, 1454, 1260, 1195, 1091, 1014,
803, 765 cm−1.
Methyl 2-(4-bromophenyl)-2-(p-tolylamino)acetate (3la). Purifi-
cation by column chromatography (EtOAc/hexane, 1:10 v/v)
afforded 3la; yellow oil (55.3 mg, yield 83%); H NMR (400 MHz,
ASSOCIATED CONTENT
■
1
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02588.
CDCl3) δ 7.34 (d, J = 6.4 Hz, 2H), 7.17 (t, J = 8.1 Hz, 4H), 6.42 (d, J
= 6.9 Hz, 2H), 4.99 (s, 2H), 3.72 (s, 3H), 2.33 (s, 3H). 13C {1H}
NMR (100 MHz, CDCl3) δ 172.2, 144.5, 138.3, 134.1, 129.8, 129.6,
129.1, 127.1, 114.5, 60.4, 52.8, 21.1. HRMS (ESI) m/z calcd for
C16H16BrNNaO2, [M + Na]+ 356.0262; found: 356.0273. IR (neat) ν
3401, 3059, 3023, 2949, 2920, 2854, 1739, 1615, 1587, 1519, 1486,
1434, 1403, 1302, 1252, 1172, 1101, 806, 745, 699 cm−1. This is
known.20h
Copies of 1H, 13C, and 19F spectra of products 3 (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Methyl 2-(3,4-dichlorophenyl)-2-(p-tolylamino)acetate (3ma).
Purification by column chromatography (EtOAc/hexane, 1:10 v/v)
Meifen Jiang − Engineering Center of Catalysis and Synthesis
for Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China; Shanghai Engineering
Center of Industrial Catalysis for Chiral Drugs, Shanghai
200433, China; Email: jiang_meifen@fudan.edu.cn
Fener Chen − Engineering Center of Catalysis and Synthesis
for Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China; Shanghai Engineering
Center of Industrial Catalysis for Chiral Drugs, Shanghai
200433, China; Institute of Pharmaceutical Science and
Technology, Zhejiang University of Technology, Hangzhou
310014, China; orcid.org/0000-0002-6734-3388;
Email: rfchen@fudan.edu.cn
1
afforded 3ma; brown oil (54.9 mg, yield 85%); H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.35 (dd,
J = 8.3, 1.7 Hz, 1H), 6.94 (d, J = 8.1 Hz, 2H), 6.44 (d, J = 8.3 Hz,
2H), 4.99 (d, J = 2.7 Hz, 1H), 4.88 (s, 1H), 3.75 (s, 3H), 2.21 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3) δ 171.4, 143.0, 138.2, 133.0,
130.8, 129.8, 129.2, 127.8, 126.5, 113.5, 60.1, 53.1, 20.4. HRMS (ESI)
m/z calcd for C16H15Cl2NNaO2, [M + Na]+ 346.0378; found:
346.0382. IR (neat) ν 3348, 3091, 2956, 2922, 2852, 1737, 1683,
1652, 1560, 1515, 1382, 1316, 1282, 1249, 1033, 814, 762 cm−1.
Methyl 2-(benzo[d][1,3]dioxol-5-yl)-2-(p-tolylamino)acetate
(3na). Purification by column chromatography (EtOAc/hexane,
1:10 v/v) afforded 3na; brown solid (47.8 mg, yield 80%), mp 86−
1
87 °C; H NMR (400 MHz, CDCl3) δ 6.94 (dd, J = 11.3, 5.1 Hz,
4H), 6.79−6.73 (m, 1H), 6.47 (d, J = 7.9 Hz, 2H), 5.90 (s, 2H), 4.95
(s, 1H), 4.80 (s, 1H), 3.71 (s, 3H), 2.19 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 172.3, 148.0, 147.5, 143.5, 131.5, 129.6, 127.2, 120.7,
113.5, 108.4, 107.4, 101.1, 60.5, 52.66, 20.30. HRMS (ESI) m/z calcd
for C17H17NNaO4, [M + Na]+ 322.1050; found: 322.1052. IR (neat)
ν 3380, 3063, 2997, 2949, 2911, 1731, 1614, 1520, 1497, 1484, 1439,
1328, 1255, 1232, 1173, 1031, 931, 914, 801 cm−1.
Authors
Sha Hu − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China; Shanghai Engineering
Center of Industrial Catalysis for Chiral Drugs, Shanghai
200433, China
Jiale Wu − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China; Shanghai Engineering
Center of Industrial Catalysis for Chiral Drugs, Shanghai
200433, China
Zuolin Lu − Institute of Pharmaceutical Science and
Technology, Zhejiang University of Technology, Hangzhou
310014, China
Jiaqi Wang − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China; Shanghai Engineering
Center of Industrial Catalysis for Chiral Drugs, Shanghai
200433, China
Ethyl p-tolylalaninate (3oa). Purification by column chromatog-
raphy (EtOAc/hexane, 1:10 v/v) afforded 3oa; colorless oil (28.2 mg,
yield 68%); 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 8.0 Hz, 2H),
6.54 (d, J = 8.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.12−4.07 (m,
1H), 2.23 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H), 1.27−1.23 (m, 3H). 13C
{1H} NMR (100 MHz, CDCl3) δ 174.8, 144.3, 129.8, 127.5, 113.6,
61.0, 52.4, 20.4, 19.0, 14.2. HRMS (ESI) m/z calcd for C12H18NO2,
[M + H]+ 208.1332; found: 208.1331. IR (neat) ν 3354, 3179, 2959,
2916, 2868, 2848, 1731, 1618, 1520, 1258, 1183, 1080, 804 cm−1
.
This is known.35
Ethyl 2-(p-tolylamino)butanoate (3pa). Purification by column
chromatography (EtOAc/hexane, 1:10 v/v) afforded 3pa; colorless
liquid (30.9 mg, yield 70%); 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J
= 8.3 Hz, 2H), 6.56 (d, J = 8.3 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H),
3.93−3.87 (m, 1H), 2.64−2.59 (m, 1H), 2.43−2.37 (m, 1H), 2.23 (s,
3H), 1.27−1.25 (m, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ
171.9, 144.5, 129.8, 127.0, 113.9, 60.4, 46.4, 41.0, 29.7, 20.6, 14.2.
HRMS (ESI) m/z calcd for C13H20NO2, [M + H]+ 222.1489; found:
Yuan Tao − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Department of Chemistry, Fudan
University, Shanghai 200433, China; Shanghai Engineering
3229
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Article
Catalyst for the Organocatalytic Hydrogenation of Ketimines. Synlett
2014, 25, 795−798.
Center of Industrial Catalysis for Chiral Drugs, Shanghai
200433, China
(8) Rueping, M.; Azap, C.; Sugiono, E.; Theissmann, T. Bro̷nsted
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02588
Acid Catalysis: Organocatalytic Hydrogenation of Imines. Synlett
2005, 2367−2369.
(9) Zhu, C.; Akiyama, T. Transfer hydrogenation of imines with
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Tetrahedron Lett. 2012, 53, 416−418.
(10) Manca, G.; Mealli, C.; Carminati, D. M.; Intrieri, D.; Gallo, E.
Comparative Study of the Catalytic Amination of Benzylic C-H Bonds
Promoted by Ru(TPP)(py)2 and Ru(TPP)(CO). Eur. J. Inorg. Chem.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Fudan University (JIH1615060).
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