Pd(II)-Catalyzed Direct ?-C(sp3)-H Arylation between Free β2-Amino Esters and β3-Amino Esters and Aryl Iodides Using a Catalytic Transient Directing Group

Article abstract of DOI:10.1021/acs.joc.0c00115

Pd(II)-catalyzed direct ?-C(sp3)-H arylation coupling with free β2-amino esters and β3-amino esters using a commercially available catalytic transient directing group has been developed. This approach features high efficiency, broad substrate tolerance, easily accessible starting materials, and mild reaction conditions.

Full text of DOI:10.1021/acs.joc.0c00115

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Article
Pd(II)-Catalyzed Directed #-C(sp3)–H Arylation between
Free #2-Amino Esters and #3-Amino Esters and Aryl
Iodides Using a Catalytic Transient Directing Group
Zhaohui Wang, Yangjie Fu, Qiyu Zhang, Hong Liu, and Jiang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00115 • Publication Date (Web): 19 May 2020
Downloaded from pubs.acs.org on May 19, 2020
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The Journal of Organic Chemistry
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Pd(II)-Catalyzed Directed γ-C(sp )–H Arylation between Free β -Amino
3
Esters and β -Amino Esters and Aryl Iodides Using a Catalytic Transient
Directing Group
Zhaohui Wang, a,b Yangjie Fu, a,b Qiyu Zhang, Hong Liu, * and Jiang Wang*,b
a,b
,a,b
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a
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing
2
10009, China
b
State Key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Supporting Information Placeholder
Pd(OAc)2
NH2
Pd(OAc)2
NH2
Ar2
NH2
Pd(PhCN) Cl2
NH2
2
Pd(PhCN) Cl2
2
Ar1
R1
R1
EtOOC R2
a-1c
TDG2
Ar1I
R2 COOEt
TDG2
Ar2I
COOEt
COOEt
4a
5a-5g
3
a-3w
1
2
3
Arylation of  -Amino Esters
3 examples, up to 77% yield
Arylation of  -Amino Esters
2
7 examples, up to 58% yield
3
2
3
ABSTRACT: Pd(II)-catalyzed directed γ-C(sp )-H arylation coupling with free β -amino esters and β -amino esters using a
commercially available catalytic transient directing group has been developed. This approach features high efficiency, broad
substrate tolerance, easily accessible starting materials and mild reaction conditions.
3
a) C(sp )-H Functionalizations of Carboxyl-terminated
INTRODUCTION
R
2
H
R
H
H2N
R
H
O
R
β-amino acids (β-AAs) are significant and rewarding
functional moieties in various peptides, peptidomimetics,
proteins, antibiotics, and other biologically active
compounds and being increasingly used in the
pharmaceutical, agrochemical, and healthcare industries.
Traditionally, the synthesis of β-AAs and their derivatives
were mainly carried out by the carbonylation of enamines.3
In recent years, using transition-metal-catalyzed direct C−H
functionalization strategy to modify simple amino acids is
H

H



DG
OH
DG
DG
DG
H N
2

H N
H2N
H2N
O
O
O
O
1
3
b) C(sp )-H Functionalizations of Amino-terminated
This Work
O
1
-2
R
R

H
H

H

H

OH
OH
OH
OH
H N
2
DG HN
DG N
H
H N
R
O
O
O
2
Recently, transient directing groups (TDGs) catalyzed
site-selective C–H functionalization have received
significant attention, due to the absence of additional
an efficient and valuable route to obtain unnatural amino
4
acids.
This C–H functionalization strategy has two
8
-9
directing groups installed and removed in situ. And free
primary amines used as substrates have been realized
pivotal methods: carboxy-terminal and amino-terminal
assisted directing groups.5-6 The former implements
2
3
3
3
Pd(II)-catalyzed γ-C(sp )-H, γ-C(sp )-H or δ-C(sp )-H
modification of α-amino acids via α-, β-, and γ-C(sp )-H
activation or β-amino acids via β- C(sp )-H activation and
the latter through γ- and δ-C(sp )-H activation to achieve
unnatural α-amino acid. A few special examples can
9
3
5
arylation by employing TDGs.
Dong et al. used
3
8-formylquinoline as exo-imine-type directing group to
achieve arylation of free primary amines. Murakami’s
9a
6
group produced γ-arylated primary amines employing
directly realize C-H functionalization by free carboxyl or
9
b
5
d,6c
salicylaldehydes as directing group. Although these two
types of aldehyde-directing groups were used in the
reaction without catalytic amount, they had the
characteristic of easily installable and removable. Yu et al.
discribed that free amines could react with the TDG
2-hydroxynicotinaldehyde producing the reversible imine
amino groups,
directing group including pyridine, 8-aminoquinoline,
-picolinamide, oxazolines, and coordinating amide
directing groups, with transition-metal forming
most of which require an additional
2
monodentate, bidentate, and tridentate metallacyclic
intermediate to achieve site-selective activation of C-H
3
3
7
intermediate to realize γ-C(sp )-H and δ-C(sp )-H
Ge and his co-workers developed the
Pd(II)-catalyzed γ-C(sp )–H arylation of primary aliphatic
bonds (Scheme 1).
9
c-9d
arylation.
3
Scheme 1. C(sp )-H Functionalizations of Amino Acids
3
amines using a catalytic amount of glycoylic acid as
9
e
TDG. And Bull’s group presented the use of novel TDG
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3
alkyl acetals as transient activators to obtain γ-C(sp )-H
applications in oxidative addition and reductive elimination
1
2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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2
2
2
2
2
2
2
3
3
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3
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4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
9f
11-12
arylation of primary amines (Scheme 2a). Recently,
Kamenecka et al. reported the cross-coupling reactions of
C(sp )-H or C(sp )-H bonds of α-amino esters with arenes
reaction.
The strategy of combining palladium with
11a, 11b
11d
11e
other metals, such as Pd/Rh
, Pd/Au , Pd/Ni
,
2
3
11d, 11f, 11g
12a, 12d, 12f
Pd/Cu
and Pd/Pd
, have been extensively
and
heteroarenes
in
the
presence
of
studied in depth. Double Pd(II)-catalyzed were commonly
used in cross-coupling reactions for example Heck reaction,
Suzuki-coupling reaction or C−H functionalization, which
can potentially lower activation barriers of chemical
9
g
2-hydroxynicotinaldehyde (Scheme 2b).
In C–H
3
activation, the transition-metal-catalyzed γ-C(sp )–H
arylation of free β-amino esters are rarely reported. At the
same time, our groups havereported a chemical method for
the resolution of racemic β -AAs and β -AAs using chiral
Ni(II)-complexes in our previous work. Therefore, various
chiral β -AAs and β -AAs can be obtained by the C–H
functionalization of simple β-AAs and chemical
resolution. Herein, we report Pd(II)-catalyzed directed
γ-C(sp )–H arylation of free β -amino esters and β -amino
esters by catalytic TDGs (Scheme 2c).
transformations compared to single Pd(II)-catalyzed
2
3
12-13
system.
A further investigation revealed that co-catalyst
and Pd(PhCN) Cl was the best
combined the Pd(OAc)
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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0
1
2
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5
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8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
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7
8
9
0
2
3
choice, affording the desired product 3a in 70% isolated
yield (Table 1, entries 18-20). Simultaneously, when the 2
equiv. or 10 equiv. of H O were additional added in the
2
1
0
3
2
3
similar reaction conditions, the yields are lower than
without water (Table 1, entries 21 and 22). And the
reaction under argon atmosphere was obtained slightly
lower yield (Table 1, entry 23). The reaction with a mixture
of HFIP and TFA was obtained 54% yield, which was
lower than using the mixture of HFIP and AcOH in the
similar reaction conditions (Table 1, entry 24).
3
Scheme 2. γ-C(sp )-H Arylation of Free Amines with
TDGs
a) Amine arylation with TDGs
3
[Pd]
Table 1. Optimizing the Conditions for γ-C(sp )-H
H
NH2
R2
R1
TDGs
additive
Ar NH2
R3
R1
2
a
Arylation of Free β -Amino Ester
R4
ArI or ArIBF4
Pd (15 mol % )
Ag salt (3 eq)
R3
R2
I
Transient Directing Groups (TDGs)
COOEt
NH2
TDG (30 mol %)
t-Bu
O
OMe
OMe
+
COOEt
NH2
O
O
H
ArO
Solvent (0.2 M)
110 °C, 12h
N
OH
·H O
OH
N
OH
O
O
t-Bu
2
Dong
Murakami
Yu
Ge
Ar
Bull
3a
1a
2a
b) Kamenecka 's work
Transient Directing Groups (TDGs)
Pd(OAc2) (15 mol %)
AgSbF6 (2 equiv.)
TDG (30 mol %)
H
+
ArI
NH2
R1
O
O
H
O
O
O
NH2
R1
HFIP:AcOH 19:1
CO2Et
N
OH
1
30°C, 12 h
· H O
OH
2
CO2Et
TDG
N
OH
OH
NH
O
c) Our work
NH2
O
TDG1
TDG2
TDG3
TDG4
NHBoc
COOH
NH2
Ar1
O
Ar1
Ar2
R1
R1
Chemical
Resolution
t-Bu
R2 COOEt
R2 COOEt
ee > 99%
O
Cl
N
OH
O
+
ArI
O
NH2
-
[Pd]
NHBoc
COOEt
[Ni]
Ar2
NH2
OH
OH
OH
t-Bu
COOEt
t-Bu
TDG6
COOH
ee > 99%
Cl
This work
Previous work
TDG5
Entry
TDG7
Yield
RESULTS AND DISCUSSION
Pd
TDG
Ag salt
Solvent
(
%)b
10
48
<5
<5
<5
<5
14
7
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(TFA)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
TDG1
TDG2
TDG3
TDG4
TDG5
TDG6
TDG7
TDG2
TDG2
TDG2
TDG2
TDG2
TDG2
TDG2
TDG2
TDG2
TDG2
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP
Initially, ethyl 3-amino-2-methylpropanoate 1a was
chosen as prototypical substrate for arylation with
4
-iodotoluene 2a due to its applicability and abundancy.
After we commenced our investigation of the reaction
conditions by screening TDGs using Pd(OAc) and AgTFA
in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 110 °C for
2 h (Table 1). Interestingly, relative to the other TDGs,
2
1
1
Ag
2
CO
3
which yielded trace product 3a, a 48% H NMR yield was
obtained when TDG2 was employed (Table 1, entries 1-7).
Using other silver salts instead of AgTFA reduced the yield
AgSbF
6
16
21
1
0
AgOAc
-
11
12
13
NR
16
32
29
11
47
16
(Table 1, entries 8-10). No reaction was observed in the
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
absence of a silver salt (Table 1, entry 11). Screening of the
solvents showed that acidic conditions could promote this
reaction, although using AcOH and TFA gained the lower
yield (Table 1, entries 12-14). Furthermore, we carried out
survey of the palladium source to optimize the reaction
conditions, however, none of them provided a better yield
AcOH
1
1
1
1
4
5
6
7
TFA
2
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:AcOH 10:1
Pd(PhCN)
Pd (dba)
Pd(OAc)
Pd(TFA)
2
Cl
2
2
3
2
,
18c
TDG2
AgTFA
HFIP:AcOH 10:1
57
than Pd(OAc)
2
(Table 1, entries 15-17)
.
In recent years,
2
cooperative metal catalytic systems produced numerous
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Pd(OAc)
Pd (dba)
Pd(OAc)
Pd(PhCN)
2
,
a,b
1
2
9c
TDG2
AgTFA
HFIP:AcOH 10:1
55
1
2
3
4
5
6
7
8
9
2
3
Pd(OAc)2 (7.5 mol % )
2
,
73
(70d)
59
0c
Pd(PhCN)2Cl2 (7.5 mol % )
TDG2 (30 mol %)
TDG2
TDG2
AgTFA
AgTFA
HFIP:AcOH 10:1
HFIP:AcOH 10:1
I
2
Cl
2
NH2
1) 1N HCl,
EtOH
NHBoc
AgTFA (3 eq)
2
1c, e
Pd(OAc)2，
R1
R2 COOEt
+
Ar1
R1
HFIP:AcOH 10:1
110 °C, 12 h
2)(Boc)2O,
TEA, DCM
R
R2 COOEt
Pd(PhCN)
Pd(OAc)2，
Pd(PhCN) Cl
Pd(OAc)2，
Pd(PhCN) Cl
Pd(OAc)2，
Pd(PhCN) Cl
2
C
l2
2
eq
2
2c, f
TDG2
TDG2
TDG2
AgTFA
AgTFA
AgTFA
HFIP:AcOH 10:1
HFIP:AcOH 10:1
HFIP:TFA 10:1
42
51
54
1
a-1c
2a-2t
3a-3v
2
2
2
2
2
3c, g
CO2Et
NHBoc
CO Et
2
CO Et
2
2
NHBoc
NHBoc
2
4c
3a, 70%
3b, 56%
3c, 69%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
t-Bu
CO2Et
CO2Et
NHBoc
CO2Et
NHBoc
a
NHBoc
Reactions were performed using 1a (0.3 mmol, 1 equiv.), 2a
(
0.6 mmol, 2 equiv.), Pd catalyst (15 mol %), silver salt (0.9
3d, 40%
3e, 59%
3f, 68%
b 1
O
mmol, 3 equiv.), TDG (30 mol %), solvent (2 mL). HNMR
yield, used 1,3,5-trimethoxybenzene as an internal standard.
Pd(OAc)
were used. Isolated yield. 2 equiv. of H
added. 10 equiv. of H
was performed under argon.
MeO
F3C
EtO2C
NHBoc
c
CO2Et
CO2Et
NHBoc
CO2Et
NHBoc
2
(7.5 mol %) and another Pd catalyst (7.5 mol %)
d
e
3h, 77%
3i, 50%
2
O was additional
3g, 45%
f
g
2
O was additional added. the reaction
NO2
NHBoc
F
CO2Et
CO2Et
NHBoc
CO2Et
NHBoc
3
j, 63%
3k, 67%
3l, 60%
CO2Me
Under optimal conditions, we next investigated the
reaction of ethyl 3-amino-2-methylpropanoate 1a with a
variety of iodides 2a-2t (Table 2). Boc protection of the
amino esters was performed in order to ease of separation
and purification. Unsubstituted iodobenzene (2b) and
various other methyl substituted aryl iodides (2c and 2d)
were firstly introduced to give the desired γ-aryl substituted
OMe
Cl
CO2Et
NHBoc
CO2Et
NHBoc
CO2Et
NHBoc
3m, 62%
CF3
3o, 62%
3n, 63%
Br
CO2Et
NHBoc
2
CO Et
CO2Et
NHBoc
NHBoc
3r, 65%
CO Et
3
p, 54%
3q, 51%
2
β -amino esters. Except o-methyl substituted which was
Ts
N
CO2Et
poorly tolerated due to steric effects, methyl substituted in
other positions and phenyl substituted aryl iodides gave
moderate to good yields (3a−3e, 40-70%). Aryl iodides
bearing electron-donating groups (t-Bu and OMe),
electron-withdrawing group (COOEt, CH
NO ), and the halogens (F and Cl) at the para-position of
the phenyl ring produced the desired products in moderate
to good yields (3f–3m, 45−77%). Moreover,
meta-substituted aryl iodides with important functional
CO Et
2
2
NHBoc
Cl
N
NHBoc
NHBoc
3
s, 74%
3t, 45%
3u, 53%
CO Et
2
NHBoc
3
CO, CF3, and
CO2Et
2
3
v, 44%
dr 1:1
a
Reactions conditions: 1a (0.3 mmol, 1 equiv.), 2 (0.6 mmol,
2 equiv.), Pd(OAc) (7.5 mol %), Pd(PhCN) Cl (7.5 mol %),
2
2
2
groups including OMe, COOMe, CF
products in moderate yields (3n–3q, 51−63%).
naphthalene iodide was also well-tolerated and gave 3r in
5% yield. Various heteroaryl iodides such as indole and
3
, and Br gave the
AgTFA (0.9 mmol, 3 equiv.), TDG2 (30 mol %), HFIP :
b
A
AcOH 10 : 1 (2 mL). Isolated yield.
6
Using ethyl 3-aminopentanoate 4a as the substrate, we
carried out the scope study on aryl iodides 2a-2g (Table 3).
Unfortunately, p-methyl iodobenzene underwent arylation
pyridine provided the desired products in 74% and 45%
yield, respectively (3s and 3t). Next，more β -amino esters
1
2
3
4
Once again, similar α-amino esters provided a 44% yield of
the isomer product (3v). Regrettably, only trace arylation
product was detected when using γ- substituted β -amino
esters- ethyl 2-(aminomethyl)-4-methylpentanoate (1d) and
ethyl 3-amino-2-benzylpropanoate (1e) as substrates.
2
b-1e as substrate underwent arylation with 4-iodotoluene
3
of β -amino esters to provide the lower yield in this case
a
under
optimal
conditions.
1b reacted
Ethyl
with
(
5a, 45%). However, a slightly increased or parallel yield
were obtained when electron-withdrawing groups COOEt
and CH CO were introduced at the para-position of the
aryl iodides, the yields were 57% and 52%, respectively
5b and 5c). Aryl iodides with meta-electron-donating
groups behaved similarly (5d, 40%). It is noteworthy that
naphthalene and heteroaryl iodides were also tolerated,
affording the desired products in moderate yields (5e-5g,
-amino-2,2-dimethylpropanoate
-iodotoluene to obtain the product in 53% yield (3u).
3
(
2
4
2%-58%).
3
2
Table 2. γ-C(sp )-H Arylation of Free β -Amino Esters
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3
2
Table 3. γ-C(sp )-H Arylation of Free β -Amino Esters
functionalization of β-amino esters. Free β -amino esters
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
and β -amino esters are shown to react with a diverse range
a,b
of simple aryl and heteroaryl iodide reagents.
Pd(OAc)2 (7.5 mol % )
Pd(PhCN)2Cl2 (7.5 mol % )
I
TDG2 (30 mol %)
AgTFA (3 eq)
1) 1N HCl,
EtOH
NHBoc
COOEt
NH2
COOEt
+
Ar2
EXPERIMENTAL SECTION
HFIP:AcOH 10:1
2)(Boc)2O,
TEA, DCM
R
General Information Unless otherwise specified, the
reagents were purchased from commercial sources, and
used without further purification. All products were
110 °C, 12 h
2
eq
4a
2a-2g
5a-5g
NHBoc
COOEt
NHBoc
COOEt
NHBoc
1
13
characterized byNMR and HRMS spectra. H and
C
COOEt
NMR spectra were recorded on a 400, 500 or 600 MHz
instrument. The chemical shifts were reported in parts per
million (ppm, δ) downfield from tetramethylsilane (TMS).
Proton coupling patterns were described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), doublet of
doublets (dd), triplet of doublets(td), doublet of triplets(dt)
and broad (br). Highresolution mass spectra (HRMS) were
measured on a Micromass Ultra Q-TOF spectrometer.
Analytical thin-layer chromatography (TLC) was
performed on HSGF 254 (0.2-0.3 mm thickness). Column
chromatography was performed on silica gel (300-400
mesh) using petroleum ether/ethyl acetate or
dichoromethane/methanol. All of the heating reactions are
carried out in oil bath.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EtO2C
O
5a, 45%
5b, 57%
5c, 52%
NHBoc
COOEt
NHBoc
COOEt
NHBoc
COOEt
Cl
N
MeO
5
d, 40%
NHBoc
COOEt
5e, 42%
5f, 43%
N
Ts
5g, 58%
a
Reactions conditions: 4a (0.3 mmol, 1 equiv.), 2 (0.6 mmol,
equiv.), Pd(OAc) (7.5 mol %), Pd(PhCN) Cl (7.5 mol %),
2
2
2
2
AgTFA (0.9 mmol, 3 equiv.), TDG2 (30 mol %), HFIP :
b
AcOH 10 : 1 (2 mL). Isolated yield.
General procedures for 1a-1e and 4a. To a solution of
β-amino acid (1.0 equiv.) in EtOH was added SOCl (1.5
2
To explore the synthetic utility of this reaction, gram-scale
synthesis of ethyl 3-((tert-butoxycarbonyl)amino)-2-(4-
methylbenzyl)propanoate 3a was promoted, which
obtained in 67% yield under optimal condition (Scheme
a). The C−H arylation of 1a with 2-fluoro-3-iodopyridine
w affording the corresponding product 3w in 48% yield
by one-pot fashion revealed that an application of this
strategy to the synthesis of bioactive fragment in
pharmaceutical research (Scheme 3b).
equiv.) dropwise at 0 °C. The resulting mixture was heated
to 90 °C for 6 h. After the solution was cooled and
concentrated in vacuo. Then the crude residue was diluted
with DCM (40 mL) and treated with ammonia hydroxide
(25-28% w/w, 10 mL),stirred at room temperature for 2 h.
The layers were separated and the aqueous layer were
washed with DCM (2 x 30 mL) , and the organic layers
were combined. The organic solution was washed by brine,
3
2
1
4
2 4
dried over anhydrous sodium sulphate (Na SO ) and
concentrated to give the desired β-amino ester as
pale-yellow oil which was used without further
purification.
General procedures for 3a-3v and 5a-5g. A tube was
2 2 2
charged with Pd(OAc) (6.4 mg, 7.5 mol %), Pd(PhCN) Cl
Scheme 3. Gram-Scale Synthesis of Compound 3a and
Synthetic Applications
a)
Pd(OAc)2 (7.5 mol % )
Pd(PhCN)2Cl2 (7.5 mol % )
TDG2 (30 mol %)
1) 1N HCl
EtOH
COOEt
NHBoc
COOEt
NH2
AgTFA (3 equiv.)
(11.0 mg, 7.5 mol %), AgTFA (252.6 mg, 1.14 mmol),
transient directing group (TDG2, 14.1 mg, 30 mol %),
+
2
) (Boc)2O
TEA, DCM
HFIP : AcOH 10 : 1
110 °C, 24 h
I
4
-iodotoluene (2a, 166 mg, 0.76 mmol) and HFIP : AcOH
1a
2a
3a
1.15g
2
0.7g
10 : 1 (2 mL), followed by the free β -amino ester (1a, 50
mg, 0.38 mmol). The reaction mixture was stirred at room
temperature for 30 minutes before heating to 110 °C for 12
hours. After that, the reaction mixture was cooled to room
temperature and the solvent was filtered through a celite
pad and washed with DCM. The solution was concentrated
under vacuum. Then EtOH (2 mL) and HCl (2 N, 1 mL)
were added to the residue, and the mixture was stirred at
room temperature for 3 h. The solvent was filtered through
a celite pad, washed with EtOH and concentrated under
vacuum. The mixture was subsequently dissolved with
6
7% Yield
b)
Pd(OAc)2 (7.5 mol % )
Pd(PhCN)2Cl2 (7.5 mol % )
TDG2 (30 mol %)
COOEt
NH2
I
COOEt
AgTFA (3 equiv.)
+
N
F
HFIP : AcOH 10 : 1
10 °C, 12 h
N
4
N
H
1
1a
2w
3w
8% Yield
CONCLUSIONS
In summary, we developed the combination of double
3
Pd(II)-catalyzed directed γ-C(sp )–H arylation of free
2
3
2
DCM (4 mL) and TEA (15 equiv.) and Boc O (4.0 equiv.)
β -amino esters and β -amino esters with aryl iodides as
coupling parteners employing a commercially available
catalytic transient directing group. This new approach
features high efficiency, broad functional tolerance, and
wild reaction conditions, which provided a variety of
unnatural β-amino acids by site-selective C–H
were added. And then the brown solution was stirred at
room temperature for 8 hours. DCM was added and the
organic layer was extracted, washed with brine, dried over
anhydrous Na
2 4
SO , and concentrated in vacuo. The residue
was purified by silica gel chromatography using petroleum
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
1
3
ether/ ethyl acetate (10:1) to afford the product 3a as a
1.19 (t, J = 7.2 Hz, 3H). C NMR (125 MHz, CDCl ) δ
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
colorless oil (yield: 70 %).
Ethyl
3-((tert-butoxycarbonyl)amino)-2-(4-methylbenzyl)prop
anoate (3a). Colorless oil (86 mg, 70 % yield, purified by
silica gel chromatography using PE/EA 20:1–6:1); H
175.8, 157.2, 138.0, 137.1, 136.1, 131.7, 131.2, 127.68,
80.8, 62.1, 48.9, 43.0, 37.0, 29.8, 21.2, 20.8, 15.6. HRMS
+
(ESI) calculated for C H NO [M+H] : 336.2169; found:
1
9
30
4
336.2174.
Ethyl
1
NMR (600 MHz, CDCl
3
) δ 7.08 (d, J = 8.0 Hz, 2H), 7.04
3-((tert-butoxycarbonyl)amino)-2-(4-(tert-butyl)benzyl)
propanoate (3f). Colorless oil (94 mg, 68 % yield, purified
(d, J = 8.0 Hz, 2H), 4.84 (d, J = 6.6 Hz, 1H), 4.10 (q, J =
7.1 Hz, 2H), 3.40 – 3.33 (m, 1H), 3.25 (dt, J = 13.9, 6.9 Hz,
1
by silica gel chromatography using PE/EA 20:1–6:1); H
1
H), 2.95 – 2.84 (m, 2H), 2.77 (dt, J = 12.2, 5.5 Hz, 1H),
NMR (600 MHz, CDCl ) δ 7.29 (d, J = 7.9 Hz, 2H), 7.09
3
1
3
1
2
.30 (s, 3H), 1.42 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H). C{ H}
) δ 174.3, 155.8, 136.0, 135.2,
29.2, 128.8, 79.3, 60.6, 47.4, 41.5, 35.5, 28.4, 21.0, 14.1.
(d, J = 8.2 Hz, 2H), 4.87 (s, 1H), 4.16 – 4.04 (m, 2H), 3.37
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (150 MHz, CDCl
1
3
(dt, J = 16.6, 4.7 Hz, 1H), 3.31 – 3.21 (m, 1H), 2.90 (d, J =
9.4 Hz, 2H), 2.78 (q, J = 10.0 Hz, 1H), 1.42 (s, 8H), 1.29 (s,
+
13
1
HRMS (ESI) calculated for C18
found: 322.2014.
Ethyl
H
28NO
4
[M+H] : 322.2013;
9H), 1.16 (dt, J = 9.7, 8.0 Hz, 3H). C{ H} NMR (125
MHz, CDCl ) δ 174.4, 155.8, 149.4, 135.2, 128.6, 125.4,
3
79.3, 60.6, 47.3, 41.6, 35.5, 34.4, 31.4, 28.4, 14.1. HRMS
+
2
-benzyl-3-((tert-butoxycarbonyl)amino)propanoate
(ESI) calculated for C H NO [M+H] : 364.2482; found:
2
1
34
4
(3b). Colorless oil (66 mg, 56 % yield, purified by silica
364.2493.
Ethyl
1
gel chromatography using PE/EA 20:1–6:1); H NMR (600
MHz, CDCl ) δ 7.29 (d, J = 7.7 Hz, 2H), 7.22 (t, J = 7.3 Hz,
H), 7.20 – 7.16 (m, 2H), 4.87 (s, 1H), 4.11 (q, J = 7.1 Hz,
3
3-((tert-butoxycarbonyl)amino)-2-(4-methoxybenzyl)pro
1
2
2
panoate (3g). Colorless oil (58 mg, 45% yield, purified by
1
H), 3.39 (s, 1H), 3.29 (d, J = 6.6 Hz, 1H), 3.03 – 2.89 (m,
H), 2.83 (d, J = 8.4 Hz, 1H), 1.44 (s, 9H), 1.18 (t, J = 7.0
silica gel chromatography using PE/EA 15:1–6:1);
H
NMR (600 MHz, CDCl ) δ 7.07 (d, J = 8.3 Hz, 2H), 6.80
3
13
1
Hz, 3H). C{ H} NMR (150 MHz, CDCl
3
) δ 174.2, 138.3,
(d, J = 8.1 Hz, 2H), 4.85 (d, J = 6.5 Hz, 1H), 4.09 (q, J =
1
28.9, 128.4, 126.5, 79.3, 60.6, 47.3, 41.6, 35.9, 28.4, 14.1.
7.1 Hz, 2H), 3.77 (d, J = 1.2 Hz, 3H), 3.35 (dt, J = 11.3,
4.9 Hz, 1H), 3.29 – 3.20 (m, 1H), 2.87 (q, J = 7.9 Hz, 2H),
2.78 – 2.70 (m, 1H), 1.42 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H).
+
HRMS (ESI) calculated for C17
found: 308.1855.
Ethyl
3-((tert-butoxycarbonyl)amino)-2-(3-methylbenzyl)prop
anoate (3c). Colorless oil (84 mg, 69 % yield, purified by
4
H26NO [M+H] : 308.1856;
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ 173.9, 157.8, 155.3,
3
129.9, 129.4, 113.4, 78.9, 60.2, 54.8, 47.1, 41.1, 34.6, 27.9,
+
13.7. HRMS (ESI) calculated for C H NO [M+H] :
1
8
28
5
1
silica gel chromatography using PE/EA 20:1–6:1); H
338.1962; found: 338.1963.
Ethyl
NMR (600 MHz, CDCl
3
) δ 7.15 (t, J = 7.5 Hz, 1H), 7.01 (d,
J = 7.6 Hz, 1H), 6.98 – 6.94 (m, 2H), 4.87 (d, J = 6.4 Hz,
4-(2-(((tert-butoxycarbonyl)amino)methyl)-3-ethoxy-3-o
xopropyl)benzoate (3h). Colorless oil (111 mg, 77 % yield,
purified by silica gel chromatography using PE/EA
1
3
2
H), 4.10 (q, J = 7.1 Hz, 2H), 3.40 – 3.31 (m, 1H), 3.29 –
.22 (m, 1H), 2.93 – 2.85 (m, 2H), 2.80 – 2.74 (m, 1H),
1
3
1
1
.31 (s, 3H), 1.42 (s, 9H), 1.19 – 1.16 (m, 3H). C{ H}
) δ 174.3, 155.8, 138.2, 138.0,
29.7, 128.4, 127.3, 125.9, 79.3, 60.6, 47.4, 41.6, 35.9,
8.4, 21.4, 14.1. HRMS (ESI) calculated for C18 28NO
4
15:1–5:1); H NMR (600 MHz, CDCl ) δ 7.96 (d, J = 8.0
3
NMR (125 MHz, CDCl
1
2
3
Hz, 2H), 7.26 – 7.19 (m, 2H), 4.90 (d, J = 6.5 Hz, 1H),
4.36 (q, J = 7.1 Hz, 2H), 4.09 (qd, J = 7.2, 2.2 Hz, 2H),
3.38 (dt, J = 11.6, 5.4 Hz, 1H), 3.28 (dt, J = 14.0, 7.0 Hz,
1H), 2.97 (ddd, J = 23.0, 14.2, 9.0 Hz, 2H), 2.87 (dd, J =
12.9, 5.9 Hz, 1H), 1.43 (s, 9H), 1.38 (t, J = 7.1 Hz, 3H),
H
+
[M+H] : 322.2013; found: 322.2015.
Ethyl
1
3
1
3
-((tert-butoxycarbonyl)amino)-2-(2-methylbenzyl)
1.17 (t, J = 7.1 Hz, 3H). C{ H} NMR (125 MHz, CDCl )
3
propanoate (3d). Colorless oil (49 mg, 40 % yield,
purified by silica gel chromatography using PE/EA
δ 173.9, 166.5, 155.8, 143.7, 129.8, 128.9, 79.5, 60.9, 60.8,
47.1, 41.7, 35.8, 28.3, 14.3, 14.1. HRMS (ESI) calculated
1
+
2
4
2
2
0:1–6:1); H NMR (600 MHz, CDCl
3
) δ 7.16 – 7.09 (m,
for C H NO [M+H] : 380.2068; found: 380.2067.
2
0
30
6
H), 4.86 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.41 – 3.29 (m,
H), 2.97 – 2.86 (m, 2H), 2.78 (dd, J = 13.1, 6.1 Hz, 1H),
Ethyl
2-(4-acetylbenzyl)-3-((tert-butoxycarbonyl)amino)propa
noate (3i). Colorless oil (66 mg, 50 % yield, purified by
13
1
.32 (s, 3H), 1.42 (s, 9H), 1.15 (t, J = 7.1 Hz, 3H). C{ H}
) δ 174.5, 155.7, 136.6, 136.1,
30.4, 129.5, 126.7, 126.0, 79.3, 60.6, 46.0, 41.7, 33.2,
8.3, 19.4, 14.1. HRMS (ESI) calculated for C18
1
NMR (150 MHz, CDCl
3
silica gel chromatography using PE/EA 20:1–6:1); H
1
2
NMR (500 MHz, CDCl ) δ 7.90 (d, J = 8.1 Hz, 2H), 7.30
3
H
27NNaO
4
(d, J = 8.3 Hz, 2H), 4.89 (s, 1H), 4.12 (qd, J = 7.1, 1.5 Hz,
+
[M+Na] : 344.1832; found: 344.1843.
2H), 3.39 (s, 1H), 3.30 (dt, J = 14.0, 6.8 Hz, 1H), 3.03 (dd,
J = 12.8, 7.6 Hz, 1H), 3.00 – 2.86 (m, 2H), 2.60 (s, 3H),
Ethyl
1
3
1
3-((tert-butoxycarbonyl)amino)-2-(3,4-dimethylbenzyl)p
ropanoate (3e). Colorless oil (75 mg, 59 % yield, purified
by silica gel chromatography using PE/EA 20:1–6:1); H
1.46 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H). C{ H} NMR (125
MHz, CDCl ) δ 196.7, 172.8, 154.8, 143.1, 134.7, 128.1,
3
1
127.6, 78.5, 59.8, 46.0, 40.6, 34.8, 27.3, 25.6, 13.1. HRMS
+
NMR (600 MHz, CDCl
d, J = 2.0 Hz, 1H), 6.88 (dd, J = 7.7, 2.0 Hz, 1H), 4.86 (d,
J = 6.5 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.39 – 3.32 (m,
H), 3.28 – 3.21 (m, 1H), 2.88 (d, J = 10.6 Hz, 2H), 2.73 (q,
J = 9.8 Hz, 1H), 2.21 (d, J = 3.8 Hz, 6H), 1.42 (s, 9H),
3
) δ 7.02 (d, J = 7.6 Hz, 1H), 6.92
(ESI) calculated for C H NNaO [M+Na] : 372.1781;
1
9
27
5
(
found: 372.1780.
Ethyl
3-((tert-butoxycarbonyl)amino)-2-(4-(trifluoromethyl)be
nzyl)propanoate (3j). White solid (90 mg, 63 % yield,
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
purified by silica gel chromatography using PE/EA
δ 174.3, 159.7, 155.8, 139.9, 129.5, 121.3, 114.6, 112.0,
79.4, 60.7, 55.1, 47.3, 41.6, 35.9, 28.4, 14.1. HRMS (ESI)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
2
0:1–6:1), m.p.:51-53 C; H NMR (600 MHz, CDCl
3
) δ
+
7
.54 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.89 (t, J
calculated for C H NO [M+H] : 338.1962; found:
1
8
28
5
= 6.4 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.38 (dt, J = 13.9,
5.5 Hz, 1H), 3.29 (dt, J = 13.9, 7.0 Hz, 1H), 3.02 – 2.83 (m,
3H), 1.43 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H). 13C{ H} NMR
338.1961.
Methyl
1
3-(2-(((tert-butoxycarbonyl)amino)methyl)-3-ethoxy-3-o
xopropyl)benzoate (3o). Colorless oil (86 mg, 62 % yield,
Purified by silica gel chromatography using PE/EA
(125 MHz, CDCl
3
) δ 173.8, 155.8, 142.6, 129.3, 128.9 (d, J
= 32.4 Hz), 125.4 (q, J = 3.8 Hz), 124.2 (q, J = 271.8 Hz),
1
9
1
79.6, 60.8, 47.1, 41.6, 35.6, 28.3, 14.1. F NMR (470 MHz,
20:1–6:1); H NMR (600 MHz, CDCl ) δ 7.89 (dt, J = 7.2,
3
CDCl
3
)
F
δ
-62.5. HRMS (ESI) calculated for
1.7 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.39 – 7.34 (m, 2H),
4.91 (d, J = 6.5 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.91 (s,
3H), 3.38 (d, J = 5.8 Hz, 1H), 3.28 (dt, J = 14.0, 6.6 Hz,
1H), 3.03 – 2.84 (m, 3H), 1.43 (s, 9H), 1.17 (t, J = 7.2 Hz,
+
C
18
H
24
3
4
NNaO [M+Na] : 398.1550; found: 398.1542.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl
-((tert-butoxycarbonyl)amino)-2-(4-nitrobenzyl)propan
3
1
3
1
oate (3k). Light yellow solid (90 mg, 67 % yield, Purified
3H). C{ H} NMR (150 MHz, CDCl ) δ 173.9, 167.0,
3
by silica gel chromatography using PE/EA 20:1–6:1), m.p.:
155.8, 138.8, 133.6, 130.3, 130.0, 128.6, 127.9, 79.5, 60.8,
o
1
6
2-63 C; H NMR (600 MHz, CDCl
3
) δ 8.18 – 8.11 (m,
52.1, 47.3, 41.6, 35.6, 28.4, 14.1. HRMS (ESI) calculated
+
2
H), 7.42 – 7.33 (m, 2H), 4.95 (t, J = 6.1 Hz, 1H), 4.10 (qq,
for C H NO [M+H] : 366.1911; found: 366.1904.
1
9
28
6
J = 7.5, 3.7 Hz, 2H), 3.45 – 3.36 (m, 1H), 3.32 (q, J = 6.9
Hz, 1H), 3.05 (dd, J = 12.9, 7.6 Hz, 1H), 2.94 (td, J = 14.2,
Ethyl
3-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethyl)be
nzyl)propanoate (3p). White solid (77 mg, 54 % yield,
purified by silica gel chromatography using PE/EA
1
2.8, 5.9 Hz, 2H), 1.44 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H).
C{ H} NMR (150 MHz, CDCl3) δ 173.5, 155.8, 146.7,
1
3
1
o
1
1
46.3, 129.8, 123.7, 79.6, 60.9, 46.9, 41.6, 35.4, 28.3, 14.1.
20:1–6:1), m.p.:52-55 C; H NMR (600 MHz, CDCl ) δ
3
+
HRMS (ESI) calculated for C17
H
24
N
2
NaO
6
[M+Na] :
7.47 (d, J = 7.4 Hz, 1H), 7.44 – 7.35 (m, 3H), 4.89 (d, J =
3
75.1527; found: 375.1531.
6.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.45 – 3.36 (m, 1H),
3.30 (dt, J = 13.8, 6.8 Hz, 1H), 3.07 – 2.79 (m, 3H), 1.43 (s,
Ethyl
13
1
3
-((tert-butoxycarbonyl)amino)-2-(4-fluorobenzyl)propa
8H), 1.15 (t, J = 7.2 Hz, 3H). C{ H} NMR (125 MHz,
noate (3l). Colorless oil (74 mg, 60 % yield, Purified by
CDCl ) δ 173.8, 155.8, 139.4, 132.4, 130.8 (d, J = 31.9 Hz),
3
1
silica gel chromatography using PE/EA 20:1–6:1);
H
128.9, 125.6 (d, J = 4.2 Hz), 124.1 (q, J = 272.1 Hz), 123.5
1
9
NMR (600 MHz, CDCl ) δ 8.18 – 8.12 (m, 2H), 7.41 –
3
(d, J = 3.7 Hz), 79.6, 60.8, 47.3, 41.7, 35.6, 28.3, 14.0. F
7.33 (m, 2H), 4.93 (d, J = 6.7 Hz, 1H), 4.10 (qd, J = 7.2,
3.8 Hz, 2H), 3.39 (dt, J = 13.7, 5.4 Hz, 1H), 3.31 (dt, J =
13.9, 6.8 Hz, 1H), 3.05 (dd, J = 12.9, 7.6 Hz, 1H), 3.01 –
NMR (470 MHz, CDCl3) δ -62.6. HRMS (ESI) calculated
+
for C H F NNaO [M+Na] : 398.1550; found: 398.1539.
1
8
24
3
4
Ethyl
1
3
1
2.89 (m, 2H), 1.44 (s, 9H), 1.18 (t, J = 7.2 Hz, 3H). C{ H}
NMR (125 MHz, CDCl ) δ 173.6, 162.2, 157.8 (d, J =
16.3 Hz), 155.3, 133.6 (d, J = 3.2 Hz), 129.9 (d, J = 7.9
Hz), 114.8 (d, J = 21.4 Hz), 79.0, 60.3, 47.0, 41.1, 34.6,
2-(3-bromobenzyl)-3-((tert-butoxycarbonyl)amino)prop
anoate (3q). Pale yellow oil (75 mg, 51 % yield, purified
3
1
6
by silica gel chromatography using PE/EA 20:1–6:1); H
NMR (600 MHz, CDCl ) δ 7.33 (d, J = 12.6 Hz, 2H), 7.14
3
1
9
2
(
7.9, 13.7. F NMR (470 MHz, CDCl3) δ -116.6. HRMS
(t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.92 (t, J =
+
ESI) calculated for C17
H
24FNNaO
4
[M+Na] : 348.1582;
6.4 Hz, 1H), 4.10 (tt, J = 9.9, 5.1 Hz, 2H), 3.43 – 3.16 (m,
2H), 2.89 (d, J = 8.9 Hz, 2H), 2.80 (t, J = 8.7 Hz, 1H), 1.43
found: 348.1574.
Ethyl
1
3
1
(s, 9H), 1.18 (t, J = 7.2 Hz, 3H). C{ H} NMR (125 MHz,
3
-((tert-butoxycarbonyl)amino)-2-(4-chlorobenzyl)prop
CDCl ) δ 173.4, 155.3, 140.3, 131.5, 129.6, 129.2, 127.1,
3
anoate (3m). Colorless oil (81 mg, 62 % yield, Purified by
122.0, 79.0, 60.3, 46.8, 41.2, 35.0, 27.9, 13.7 HRMS (ESI)
1
+
silica gel chromatography using PE/EA 20:1–6:1);
H
calculated for C H BrNNaO [M+Na] : 408.0781; found:
1
7
24
4
NMR (600 MHz, CDCl ) δ 7.25 – 7.22 (m, 2H), 7.12 –
3
408.0773.
Ethyl
7
3
7
7
1
3
C
.08 (m, 2H), 4.86 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.41 –
.31 (m, 1H), 3.25 (dt, J = 14.1, 7.3 Hz, 1H), 2.88 (h, J =
.7 Hz, 2H), 2.81 – 2.71 (m, 1H), 1.42 (s, 9H), 1.17 (t, J =
3-((tert-butoxycarbonyl)amino)-2-(naphthalen-2-ylmeth
yl)propanoate (3r). Colorless oil (89 mg, 65 % yield,
purified by silica gel chromatography using PE/EA
13
1
3
.1 Hz, 3H). C{ H} NMR (150 MHz, CDCl ) δ 173.5,
1
55.3, 136.4, 131.9, 129.8, 128.1, 79.0, 60.3, 46.8, 41.1,
4.7, 27.9, 13.7. HRMS (ESI) calculated for
12:1–4:1); H NMR (600 MHz, CDCl ) δ 7.81 – 7.72 (m,
3
3H), 7.61 (d, J = 1.9 Hz, 1H), 7.43 (pd, J = 6.9, 1.5 Hz,
2H), 7.30 (dd, J = 8.4, 1.8 Hz, 1H), 4.91 (t, J = 6.4 Hz, 1H),
4.08 (q, J = 7.2 Hz, 2H), 3.46 – 3.37 (m, 1H), 3.31 (dt, J =
14.1, 7.3 Hz, 1H), 3.10 (dd, J = 12.9, 7.3 Hz, 1H), 2.99
(ddt, J = 19.5, 12.8, 7.0 Hz, 2H), 1.42 (s, 9H), 1.12 (t, J =
+
17
H
24ClNNaO
4
[M+Na] : 364.1286; found: 364.1290.
Ethyl
3-((tert-butoxycarbonyl)amino)-2-(3-methoxybenzyl)pro
panoate (3n). Colorless oil (81 mg, 63 % yield, Purified by
1
13
1
silica gel chromatography using PE/EA 20:1–6:1);
NMR (600 MHz, CDCl
H
7.2 Hz, 3H). C{ H} NMR (125 MHz, CDCl ) δ 174.3,
3
3
) δ 7.18 (t, J = 7.9 Hz, 1H), 6.75
155.8, 135.9, 133.5, 132.3, 128.2, 127.6, 127.6, 127.4,
(ddd, J = 8.4, 3.3, 1.7 Hz, 2H), 6.72 – 6.70 (m, 1H), 4.88 (d,
J = 6.5 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H),
127.2, 126.0, 125.5, 79.4, 60.7, 47.4, 41.8, 36.1, 28.4, 14.1.
+
HRMS (ESI) calculated for C H NO [M+H] : 358.2013;
21 28
4
3
.43 – 3.33 (m, 1H), 3.28 (dd, J = 13.6, 6.8 Hz, 1H), 2.92
found: 358.2003 .
Ethyl
3-((tert-butoxycarbonyl)amino)-2-((1-tosyl-1H-indol-5-y
(
1
d, J = 10.7 Hz, 2H), 2.79 (d, J = 7.4 Hz, 1H), 1.42 (s, 9H),
1
3
1
.19 (t, J = 7.2 Hz, 3H). C{ H} NMR (150 MHz, CDCl
3
)
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
+
l)methyl)propanoate (3s). White solid (141 mg, 74 %
yield, purified by silica gel chromatography using PE/EA
21 32 6
C H NO [M+H] : 394.2224; found: 394.2227.
Ethyl
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
1
2:1–4:1), m.p.: 41-43 C; H NMR (600 MHz, CDCl
3
) δ
3-((tert-butoxycarbonyl)amino)-5-(p-tolyl)pentanoate
(5a). White solid (66 mg, 45 % yield, purified by silica gel
chromatography using PE/EA 12:1–4:1), m.p.: 71-73 C;
7.87 (d, J = 8.5 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.52 (d, J =
3.7 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 8.2 Hz,
2H), 7.11 (dd, J = 8.5, 1.7 Hz, 1H), 6.57 (d, J = 3.7 Hz,
1H), 4.86 (t, J = 6.4 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.36
(dt, J = 12.0, 5.2 Hz, 1H), 3.25 (dt, J = 14.1, 7.2 Hz, 1H),
2.98 (dd, J = 12.9, 7.3 Hz, 1H), 2.94 – 2.82 (m, 2H), 2.33
o
1
H NMR (500 MHz, CDCl δ 7.10 (s, 2H), 7.09 (d, J = 8.4
3
Hz, 2H), 5.01 (d, J = 8.9 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H),
3.99 (d, J = 14.2 Hz, 1H), 2.73 – 2.47 (m, 4H), 2.32 (d, J =
14.3 Hz, 3H), 1.90 – 1.76 (m, 2H), 1.47 (s, 8H), 1.28 (d, J
= 7.1 Hz, 3H). C{ H} NMR (125 MHz, CDCl ) δ 171.7,
155.4, 138.4, 135.4, 129.1, 128.2, 79.3, 60.6, 47.5, 39.4,
1
3
1
13
1
(
s, 3H), 1.42 (s, 9H), 1.07 (t, J = 7.2 Hz, 3H). C{ H}
NMR (125 MHz, CDCl ) δ 173.8, 155.4, 144.4, 134.9,
33.2, 133.0, 130.6, 129.4, 126.4, 126.2, 125.2, 121.0,
13.0, 108.4, 79.0, 60.2, 47.2, 41.2, 35.3, 27.9, 21.1, 13.6.
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
1
36.6, 32.1, 28.4, 21.0, 14.2. HRMS (ESI) calculated for
C H NNaO [M+Na] : 358.1989; found: 358.1989.
+
1
9
29
4
+
HRMS (ESI) calculated for C26
H
32
N
2
NaO
6
S [M+Na] :
Ethyl
5
23.1873; found: 523.1871.
Ethyl
4-(3-((tert-butoxycarbonyl)amino)-5-ethoxy-5-oxopentyl)b
enzoate (5b). Colorless oil (77 mg, 57 % yield, purified by
1
3
-((tert-butoxycarbonyl)amino)-2-((6-chloropyridin-2-yl)m silica gel chromatography using PE/EA 12:1–4:1);
H
ethyl)propanoate (3t). Colorless oil (59 mg, 45 % yield,
purified by silica gel chromatography using PE/EA
1
NMR (500 MHz, CDCl ) δ 8.02 – 7.94 (m, 2H), 7.28 –
3
7.24 (m, 2H), 5.05 (d, J = 9.4 Hz, 1H), 4.38 (q, J = 7.1 Hz,
1
0:1–4:1); H NMR (600 MHz, CDCl
3
) δ 7.55 (t, J = 7.7
2H), 4.15 (q, J = 7.1 Hz, 2H), 3.98 (s, 1H), 2.86 – 2.65 (m,
2H), 2.54 (td, J = 15.6, 13.9, 5.4 Hz, 2H), 1.99 – 1.78 (m,
2H), 1.47 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1
Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.13 – 7.07 (m, 1H),
4
2
1
.98 (s, 1H), 4.12 (qd, J = 7.1, 2.3 Hz, 2H), 3.41 – 3.33 (m,
H), 3.17 – 3.11 (m, 2H), 2.97 (q, J = 5.7, 5.1 Hz, 1H),
13
1
Hz, 3H). C{ H} NMR (125 MHz, CDCl ) δ 171.1, 166.1,
3
13
1
.42 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H). C{ H} NMR (150
) δ 173.7, 159.6, 155.8, 150.7, 139.0, 122.1,
9.3, 60.8, 45.1, 41.2, 36.9, 28.3, 14.1. HRMS (ESI)
154.9, 146.4, 129.3, 127.9, 78.9, 60.3, 60.1, 46.9, 38.9,
MHz, CDCl
7
calculated for C16
343.1412 .
3
35.6, 32.2, 27.9, 13.9, 13.7. HRMS (ESI) calculated for
+
21 32 6
C H NO [M+H] : 394.2224; found: 394.2222.
+
H
24ClN
2
O
4
[M+H] : 343.1419; found:
Ethyl
5-(4-acetylphenyl)-3-((tert-butoxycarbonyl)amino)
Ethyl
pentanoate (5c). Colorless oil (65 mg, 52 % yield, purified
1
3-((tert-butoxycarbonyl)amino)-2-methyl-2-(4-methylbe
nzyl)propanoate (3u). Colorless oil (61 mg, 53 % yield,
purified by silica gel chromatography using PE/EA
20:1–6:1); H NMR (500 MHz, CDCl
Hz, 2H), 6.99 – 6.94 (m, 2H), 4.89 (s, 1H), 4.13 (qd, J =
by silica gel chromatography using PE/EA 12:1–4:1); H
NMR (600 MHz, CDCl ) δ 7.95 – 7.83 (m, 2H), 7.29 (d, J
3
= 8.1 Hz, 2H), 5.06 (d, J = 9.5 Hz, 1H), 4.15 (q, J = 7.1 Hz,
1
3
) δ 7.05 (d, J = 7.7
2H), 3.98 (p, J = 6.5, 4.6 Hz, 1H), 2.75 (dddd, J = 30.3,
13.9, 10.8, 6.3 Hz, 2H), 2.59 (s, 3H), 2.54 (td, J = 17.1,
15.6, 5.3 Hz, 2H), 1.95 – 1.78 (m, 2H), 1.46 (s, 9H), 1.26 (t,
7
3
2
.2, 2.9 Hz, 2H), 3.30 (dd, J = 13.7, 5.5 Hz, 1H), 3.27 –
.20 (m, 1H), 2.88 – 2.79 (m, 2H), 2.30 (s, 3H), 1.43 (d, J =
.0 Hz, 9H), 1.25 (d, J = 7.0 Hz, 3H), 1.15 (s, 3H). C{ H}
1
3
1
J = 7.1 Hz, 3H). C{ H} NMR (150 MHz, CDCl ) δ 197.8,
3
1
3
1
171.5, 155.3, 147.3, 135.1, 128.6, 128.6, 79.4, 60.6, 47.2,
NMR (125 MHz, CDCl
3
) δ 175.7, 155.7, 135.8, 133.0,
39.3, 36.0, 32.6, 28.3, 26.6, 14.1. HRMS (ESI) calculated
+
1
1
3
29.5, 128.4, 78.7, 60.3, 47.9, 46.4, 42.3, 27.9, 20.6, 19.8,
for C H NO [M+H] : 364.2118; found: 364.2114.
2
0
30
5
+
3.9. HRMS (ESI) calculated for C19
36.2169; found: 336.2172.
Diethyl
H
30NO
4
[M+H] :
Ethyl
3-((tert-butoxycarbonyl)amino)-5-(3-methoxyphenyl)pe
ntanoate (5d). White solid (48 mg, 40 % yield, purified by
silica gel chromatography using PE/EA 12:1–4:1), m.p.:
2
-((tert-butoxycarbonyl)amino)-3-(4-methylbenzyl)succi
o
1
nate (3v). Colorless oil (isomer-1 23 mg, isomer-2 20 mg,
4 % yield, purified by silica gel chromatography using
70-72 C; H NMR (500 MHz, CDCl ) δ 7.24 – 7.19 (m,
3
4
1H), 6.80 (dt, J = 7.7, 1.2 Hz, 1H), 6.77 – 6.74 (m, 2H),
1
PE/EA 20:1–6:1); H NMR (600 MHz, CDCl
3
) δ 7.10 (s,
H), 5.56 (d, J = 9.9 Hz, 1H), 4.41 (dd, J = 9.9, 3.8 Hz, 1H),
.23 – 4.06 (m, 4H), 3.30 (td, J = 7.6, 3.7 Hz, 1H), 3.04 (dd,
5.02 (d, J = 8.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.99 (q,
J = 13.9, 10.0 Hz, 1H), 3.82 (s, 3H), 2.76 – 2.62 (m, 2H),
2.55 (dt, J = 15.6, 7.6 Hz, 2H), 1.91 – 1.80 (m, 2H), 1.47 (s,
4
4
13
J = 13.9, 7.2 Hz, 1H), 2.80 (dd, J = 13.9, 8.2 Hz, 1H), 2.31
9H), 1.28 (t, J = 7.1 Hz, 3H). C NMR (125 MHz, CDCl )
3
(s, 3H), 1.48 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 1.18 (t, J =
δ 173.04, 161.12, 156.79, 144.58, 130.82, 122.17, 115.55,
13
1
7
.1 Hz, 3H). C{ H} NMR (125 MHz, CDCl
3
) δ 172.6,
112.75, 80.70, 78.69, 61.97, 48.89, 40.80, 37.79, 34.07,
1
3
1
170.9, 155.4, 135.8, 134.5, 128.8, 128.5, 79.5, 61.0, 60.6,
53.2, 48.2, 33.9, 27.9, 20.6, 13.6, 13.2. H NMR (600 MHz,
Chloroform-d) δ 7.08 (s, 4H), 5.29 (d, J = 8.9 Hz, 1H), 4.62
(dd, J = 8.6, 5.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.14 –
3.99 (m, 2H), 3.15 (s, 1H), 3.06 (dd, J = 13.8, 9.3 Hz, 1H),
2.79 (dd, J = 14.0, 5.9 Hz, 1H), 2.30 (s, 3H), 1.44 (s, 9H),
29.82, 15.61. C{ H} NMR (150 MHz, CDCl ) δ 197.8,
3
1
171.5, 155.3, 147.3, 135.1, 128.6, 128.5, 79.4, 60.6, 47.2,
39.3, 36.0, 32.6, 28.3, 26.5, 14.1. HRMS (ESI) calculated
+
for C H NO [M+H] : 352.2118; found: 352.2120
1
9
30
5
Ethyl
3-((tert-butoxycarbonyl)amino)-5-(naphthalen-2-yl)pent
anoate (5e). White solid (54 mg, 42 % yield, purified by
silica gel chromatography using PE/EA 12:1–4:1), m.p.:
1
3
1
1
.29 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). C{ H}
NMR (125 MHz, CDCl ) δ 172.0, 170.7, 155.1, 136.1,
35.3, 129.1, 128.9, 80.1, 61.72, 61.0, 54.6, 50.1, 33.5,
8.3, 21.0, 14.2, 14.0. HRMS (ESI) calculated for
3
o
1
1
2
78-80 C; H NMR (500 MHz, CDCl ) δ 7.82 (dd, J = 7.5,
3
1.4 Hz, 1H), 7.81 – 7.78 (m, 2H), 7.65 (d, J = 1.7 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
7
.46 (dqd, J = 8.1, 6.9, 1.5 Hz, 2H), 7.35 (dd, J = 8.4, 1.7
to afford the product 3a as a colorless oil (1.15 g yield: 67
%).
General procedure for compound 3w. A tube was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, 1H), 5.14 – 5.02 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H),
4
(q, J = 10.7, 8.6 Hz, 2H), 2.05 – 1.91 (m, 1H), 1.49 (s, 8H),
1.27 (t, J = 7.1 Hz, 3H). C{ H} NMR (125 MHz, CDCl
δ 173.1, 156.8, 140.5, 135.1, 133.5, 129.4, 129.0, 128.9,
128.6, 127.8, 127.4, 126.6, 80.7, 62.0, 49.0, 40.8, 37.8,
34.2, 29.8, 15.6. HRMS (ESI) calculated for C22
[M+H] : 372.2169; found: 372.2166.
.04 (q, J = 14.8, 12.4 Hz, 1H), 2.97 – 2.80 (m, 2H), 2.58
charged with Pd(OAc) (6.4 mg, 7.5 mol %), Pd(PhCN) Cl
2
2
2
1
3
1
3
)
(11.0 mg, 7.5 mol %), AgTFA (252.6 mg, 1.14 mmol),
transient directing group (TDG2, 14.1 mg, 30 mol%),
2-fluoro-3-iodopyridine (2w, 170 mg, 0.76 mmol) and
2
H
30NO
4
HFIP : AcOH 10:1 (2 mL), followed by the free β -amino
+
ester (1a, 50 mg, 0.38 mmol). The reaction mixture was
stirred at room temperature for 30 minutes before heating
to 110 °C for 12 hours. After that, the reaction mixture was
cooled to room temperature and the solvent was filtered
through a celite pad and washed with DCM. The solution
was concentrated under vacuum. Then EtOH (2 mL) and
HCl (2 N, 1 mL) were added to the residue and the mixture
was stirred at room temperature for 3 h. The solvent was
filtered through a celite pad, washed with EtOH and
concentrated under vacuum. DCM was added and the
organic layer was extracted, washed with brine, dried over
anhydrous Na SO , and concentrated in vacuo. The residue
Ethyl
3
-((tert-butoxycarbonyl)amino)-5-(6-chloropyridin-2-yl)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
pentanoate (5f). White solid (47 mg, 43 % yield, purified
by silica gel chromatography using PE/EA 10:1–3:1), m.p.:
o
1
9
1
5
2
2
3
0-92 C; H NMR (500 MHz, CDCl ) δ 7.56 (t, J = 7.7 Hz,
H), 7.15 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H),
.09 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.97 (s, 1H), 2.93 –
.75 (m, 2H), 2.54 (dd, J = 5.7, 1.9 Hz, 2H), 2.00 – 1.90 (m,
H), 1.44 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H). C{ H} NMR
) δ 171.5, 162.3, 155.4, 150.8, 139.1,
21.7, 79.3, 60.6, 47.4, 39.6, 34.6, 28.4, 14.2. HRMS (ESI)
1
3
1
(125 MHz, CDCl
3
1
2
4
+
calculated for C17
H
26ClN
2
O
4
[M+H] : 357.1576; found:
was purified by silica gel chromatography using DCM/
MeOH (10:1) to afford the product 3w as a white solid
(yield: 48 %).
3
57.1571.
Ethyl
3
-((tert-butoxycarbonyl)amino)-5-(1-tosyl-1H-indol-5-yl)p
Ethyl
entanoate (5g). White solid (103 mg, 58 % yield, purified
by silica gel chromatography using PE/EA 10:1–3:1), m.p.:
1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate
(3w). White solid (38 mg, 48 % yield, purified by silica gel
chromatography using DCM/MeOH 20:1–10:1), m.p.:
o
1
4
3
3-45 C; H NMR (500 MHz, CDCl ) δ 7.90 (d, J = 8.5
o
1
Hz, 1H), 7.80 – 7.74 (m, 2H), 7.54 (d, J = 3.7 Hz, 1H),
7.34 (d, J = 1.6 Hz, 1H), 7.25 – 7.21 (m, 2H), 7.15 (dd, J =
8.5, 1.7 Hz, 1H), 6.60 (dd, J = 3.7, 0.8 Hz, 1H), 5.02 (d, J
= 9.3 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 7.0 Hz,
1H), 2.82 – 2.66 (m, 2H), 2.60 – 2.48 (m, 2H), 2.36 (s, 3H),
1.93 – 1.79 (m, 2H), 1.46 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H).
57-59 C; H NMR (600 MHz, CDCl ) δ 7.84 (s, 1H), 7.28
3
(dp, J = 7.3, 1.1 Hz, 1H), 6.57 (dd, J = 7.2, 5.2 Hz, 1H),
5.67 (s, 1H), 4.19 (qd, J = 7.1, 1.2 Hz, 2H), 3.69 (dt, J =
12.0, 3.7 Hz, 1H), 3.54 (ddd, J = 12.0, 9.0, 1.4 Hz, 1H),
3.00 (d, J = 7.3 Hz, 2H), 2.93 – 2.86 (m, 1H), 1.27 (t, J =
1
3
7.1 Hz, 3H). C NMR (150 MHz, CDCl ) δ 172.5, 154.3,
3
1
3
1
C{ H} NMR (125MHz, CDCl
3
) δ 171.6, 155.4, 144.8,
142.8, 137.8, 115.8, 112.7, 61.1, 42.9, 37.0, 28.9, 14.1.
+
1
1
2
36.7, 135.4, 133.4, 131.0, 129.9, 126.8, 126.5, 125.3,
20.7, 113.4, 108.9, 79.3, 60.6, 47.4, 39.4, 36.9, 32.4, 28.4,
1.6, 14.2. HRMS (ESI) calculated for C27H N O S
35 2 6
HRMS (ESI) calculated for C H N O [M+H] : 207.1128;
11 15
2
2
found: 207.1122 .
+
[
M+H] : 515.2210; found: 515.2210.
Gram-scale synthesis of compound 3a. A tube was
charged with Pd(OAc) (89.9 mg, 7.5 mol %),
Pd(PhCN) Cl (153.5 mg, 7.5 mol %), AgTFA (3.54 g,
6.0 mmol), transient directing group (TDG2, 197.1 mg, 30
ASSOCIATED CONTENT
Supporting Information
2
2
2
The Supporting Information is available free of charge on
the ACS Publications website at http://pubs.acs.org.
1
mol %), 4-iodotoluene (2a, 2.33 g, 10.7 mmol) and HFIP :
AcOH 10 : 1 (30 mL), followed by the free β-amino ester
1
13
1
19
Copies of H NMR, C { H} NMR, and F NMR Spectra
spectra for all compounds.
(1a, 0.7 g, 5.3 mmol). The reaction mixture was stirred at
room temperature for 30 minutes before heating to 110 °C
for 24 hours. After that, the reaction mixture was cooled to
room temperature and the solvent was filtered through a
celite pad and washed with DCM. The solutions were
concentrated under vacuum. Then EtOH (50 mL) and HCl
AUTHOR INFORMATION
Corresponding Authors
*
*
E-mail: hliu@simm.ac.cn (H. L.).
E-mail: jwang@simm.ac.cn (J. W.).
(2 N, 15 mL) were added to the residue and the mixture
was stirred at room temperature for 3 h. The solvent was
filtered through a celite pad, washed with EtOH and
concentrated under vacuum. The mixture was subsequently
dissolved with DCM (80 mL) and TEA (15 equiv.) and
Boc O (4.0 equiv.) were added. And then the brown
2
solution was stirred at room temperature for 8 hours. DCM
was added and the organic layer was extracted, washed
with brine, dried over anhydrous Na SO , and concentrated
2 4
in vacuo. The residue was purified by silica gel
chromatography using petroleum ether/ ethyl acetate (10:1)
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science
Foundation of China (81620108027, 21632008, and
2
1877118) and supported by grants from Science and
Technology Commission of Shanghai Municipality
17431903100 and 18431907100).
(
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