Free Amino Group-Directed γ-C(sp3)-H Arylation of α-Amino Esters with Diaryliodonium Triflates by Palladium Catalysis

Article abstract of DOI:10.1021/acs.joc.9b00605

Free amino group-directed C(sp³)-H functionalization of aliphatic amines is a fundamental challenge in synthetic organic chemistry. Also, the NH₂-directed C(sp³)-H functionalization of α-amino acids and their derivatives remains barely explored. With palladium as the catalyst and Ag₂O as the additive, we developed the first NH₂-directed γ-C(sp³)-H arylation of α-amino esters with diaryliodonium triflates for the construction of synthetically useful γ-aryl-α-amino esters, and the result of the KIE study suggested that the catalytic reaction involved an irreversible C-H cleavage as the rate-determining step.

Full text of DOI:10.1021/acs.joc.9b00605

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Article
Free Amino Group-Directed #-C(sp3)-H Arylation of #-Amino
Esters with Diaryliodonium Triflates by Palladium Catalysis
Pranab K. Pramanick, Zhibing Zhou, Zhen-Lin Hou, and Bo Yao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00605 • Publication Date (Web): 08 Apr 2019
Downloaded from http://pubs.acs.org on April 8, 2019
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Free Amino Group-Directed γ-C(sp )-H Arylation of
α-Amino Esters with Diaryliodonium Triflates by
Palladium Catalysis
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1,2
Pranab K. Pramanick, Zhibing Zhou, Zhen-Lin Hou and Bo Yao *
1MOE Key Laboratory of Cluster Science, Beijing Key Laboratory of Photoelectronic/
Electrophotonic Conversion Materials, School of Chemistry and Chemical Engineering, Beijing
Institute of Technology, Beijing 102488, P. R. China.
2Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
1
*
00190, P.R. China.
E-mail: yaobo@bit.edu.cn
3
ABSTRACT: Free amino group-directed C(sp )-H functionalization of aliphatic amines is a
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fundamental challenge in synthetic organic chemistry. And the NH -directed C(sp )-H
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functionalization of α-amino acids and their derivatives remains barely explored. With palladium
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as the catalyst and Ag O as the additive, we developed the first NH -directed γ-C(sp )-H
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arylation of α-amino esters with diaryliodonium triflates for the construction of synthetically
useful γ-aryl-α-amino esters. And the result of KIE study suggested that the catalytic reaction
involved an irreversible C-H cleavage as the rate-determining step.
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. INTRODUCTION
α-Amino acids (α-AAs) are an important class of versatile compounds having broad applications
1
2
in both of chemical and biological areas. Among the existing methods for amino acid synthesis,
direct modification of readily available α-AAs by C-H functionalization of side chains represents
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3
one of the most efficient and straightforward strategies. However, activation of the inert C(sp )-
H bonds at the β, γ and δ-positions often required various directing auxiliaries linked to the
amino4,5 or carboxyl groups (Scheme 1).6,7 The pre-installation of these auxiliaries and the
removal of them after functionalization made these methods atom- and step-uneconomical.
Therefore, development of novel methods using free amino or carboxyl groups as directing
3
groups in the C(sp )-H functionalization of α-AAs would be very desirable. An early example
3
was the Pt-catalyzed γ-C(sp )-H hydroxylation of unprotected natural α-AAs developed by
8
Sames. However, the low yield and moderate chemo/regio-selectivities in the reaction limited
3
its application. In recent years, β-C(sp )-H functionalization of α-AAs directed by free carboxyl
9
10
groups (COOH) had also been developed by Yu and Zhao. But so far, free amino group-
3
directed functionalization of inert C(sp )-H bonds of α-AAs remained underdeveloped (Scheme
1
).
3
Scheme 1. Directing groups strategies for inert C(sp )-H functionalization of α-AAs
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H
NPhth
H
H
Aux/PG
NPhth


H
H


HN

NH2
CO R

Aux
R

COOH
CO R
2
H
O
2
H
Well-developed
Underdeveloped
The past several decades has witnessed great advances in transition metal-catalyzed directing
group-promoted C-H activation.11 Compared with other N-containing functional groups, free
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amino groups had been far less useful as directing groups in C-H activation. The scope of free
1
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amino group-directed C-H functionalization is mainly restricted to anilines, benzylamines, β-
1
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arylethylamines and sterically bulky secondary amines. Using the steric tethering strategy,
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Gaunt reported the free amino group-directed β- and γ-C(sp )-H arylation of sterically hindered
secondary amines in 2015 (Scheme 2a).15a-15b Compared with secondary amino groups, the
16
smaller NH group is more prone to forming less active bis-amine complexes with metals. To
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suppress the formation of bis-amine complexes, Shi designed a protonation strategy17 and
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realized the NH -directed γ-C(sp )-H acetoxylation of aliphatic amines. Meanwhile, γ- and δ-
2
3
C(sp )-H arylation of primary aliphatic amines had also been developed by several groups using
1
9
transient directing strategies (Scheme 2b). It was shown that the yield was dramatically reduced
in the absence of these transient ligands even when the reactions were performed under acidic
conditions.19d,19f,19h Hence, the NH -directed γ-C(sp )-H arylation of primary aliphatic amines
3
2
remains to be an unconquered task. In this context and in connection with our interest in C-H
3
functionalization of α-AAs, we herein report an efficient NH -directed γ-C(sp )-H arylation of α-
2
amino esters with diaryliodonium triflates by palladium catalysis (Scheme 2c). Both Ag O and
2
the HFIP/AcOH co-solvent system were very essential for the chemistry. Aryl groups with
diverse functional groups were selectively installed to a wide range of α-amino esters in
moderate to good yield.
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Scheme 2. Arylation of inert C(sp )-H bonds of free aliphatic amines
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a) - or -C(sp )-H arylation of sterically hindered secondary amines
directed by free amino group
Gaunt (2015)15b,15c
cat. [Pd]
R
R
or
N
N
Ar-Bpin
N
R
N
H
R
H
H
Ar(Mes)IOTf
H
H
H
Ar
Ar
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b) - or -C(sp )-H arylation of primary aliphatic amines and amino
esters enabled by transient ligands
Dong,19a Yu,19b-c Ge,19d Murakami,19e Young,19f Kamenecka,19g
and Bull19h
cat. [Pd], additives
R
+
Ar2IBF4
or ArI
R
Transient ligand
NH2
n
H
NH2
n
Ar
3
c) -C(sp )-H arylation of -amino esters directed by free amino group
This work:
NH2
R
cat. Pd(OAc)2
NH2
R
Ag O
2
+
Ar2IOTf
EtO C
Ar
EtO C
H
2
2
HFIP/AcOH
R1
R1
R2
R2
2. RESULT AND DISCUSSION
The study was commenced with exploring the reaction of α-ethylated alanine ethyl ester 1a with
PhI (Table 1). After a short survey of reaction parameters, the desired γ-C-H arylation product 2a
was obtained in 19% yield when 1a was treated with 10 mol% Pd(OAc) , 0.75 equiv Ag O and
2
2
3
.0 equiv PhI in HFIP/AcOH (85/15, 0.2 M) at 120 C for 12 h (Entry 1, Table 1). As efforts on
further improving the yield of this reaction failed, other arylation reagents were tested. The
reaction of 1a with phenylboronic acid using AgOAc as the oxidant did not give any product
(
Entry 2, Table 1), while the reaction with diphenyliodonium triflate (Ph IOTf) delivered 2a in a
2
little higher yield (Entry 3, Table 1). Then, the conditions optimization was continued with
Ph IOTf as the arylation reagent. Considering that triflic acid (TfOH) was a major by-product in
2
the reaction, we envisioned that the use of a basic additive as the scavenger might be helpful to
the reaction.15b,19a Among a wide range of basic additives screened, 2,6-di-tert-butylpyridine
(
DTBP) and NaHCO gave reduced yield of 2a (Entries 4 and 5,Table 1), while other bases
3
including iPr EtN, K CO , NaOAc and copper salts (CuF , CuOAc) killed the reaction
2
2
3
2
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completely (see Table S1 in SI). Gratifyingly, basic silver compounds were found to be
beneficial to the reaction and Ag O gave the optimal result (Entries 6-9, Table 1). Moreover, the
2
HFIP/AcOH co-solvent system was very crucial to the reaction (Entries 12 and 13, Table 1).
Using pure AcOH as the solvent led to only 17% yield of 2a. On the other hand, the reaction in
pure HFIP gave no product, although using AgOAc instead led to 19% yield of 2a. After further
investigation of reaction parameters such as the temperature, concentration, reaction time and
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others (Table S1 in SI), the optimal conditions for the γ-C(sp )-H arylation of 1a was determined
as: 1a (0.2 mmol), Ph IOTf (1.5 equiv), Ag O (0.75 equiv) and Pd(OAc) (10 mol%) in
2
2
2
HFIP/AcOH (85/15, 0.1 M) at 100 ºC under air atmosphere for 24 hours (entry 6, Table 1). It is
needed to mention that a latger scale reaction of 1a (1.0 mmol) under the optimal conditions
furnished 2a in 64% yield.
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Table 1. Conditions optimization for C(sp )-H arylation of amino ester 1a.
NH2
H
NH2 Ph
Conditionsa
+
[Ph]
EtO C
2
EtO C
2
1a
2a
Entry
[Ph] (equiv)
PhI (3.0)
Additive (equiv)
Yield
19%
n.d.
1c
2c
3c
4
Ag O (0.75)
2
PhB(OH) (3.0)
AgOAc (1.5)
-
2
Ph IOTf (1.5)
25%
20%
2
Ph IOTf (1.5)
DTBP (1.5)
2
5
Ph IOTf (1.5)
NaHCO (1.5)
10%
2
3
72%(64%)b
6
Ph IOTf (1.5)
Ag O (0.75)
2
2
7
Ph IOTf (1.5)
AgOAc (1.5)
Ag CO (1.5)
59%
29%
11%
2
8
Ph IOTf (1.5)
2
2
3
9
Ph IOTf (1.5)
AgOTf (1.5)
2
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0
Ph IOTf (1.5)
Ag O (1.5)
53%
65%
n.d.
2
2
1
1c
2d
3d
4e
5 f
Ph IOTf (1.5)
Ag O (0.75)
2
2
1
1
1
1
Ph IOTf (1.5)
Ag O (0.75)
2
2
Ph IOTf (1.5)
AgOAc (1.5)
19%
17%
n.d.
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0
Ph IOTf (1.5)
Ag O (0.75)
2
2
Ph IOTf (1.5)
Ag O (0.75)
2
2
a
Conditions: 1a (0.2 mmol), [Ph], Pd(OAc) (10 mol%), additive, HFIP/AcOH (85/15, 2 mL),
air, 100 C, 24 h. 1.0 mmol scale reaction. HFIP/AcOH (85/15, 1 mL), 120 C, 12 h. HFIP (2
mL). AcOH (2 mL). No Pd(OAc) . n.d. = not determined, DTBP = 2,6-di-tert-butylpyridine,
2
b
c
d
e
f
2
HFIP = 1,1,1,3,3,3-Hexafluoroisopropanol.
With the optimal conditions in hand, the scope of α-amino esters was first explored (Scheme 3).
For ease of purification, the products were isolated as the corresponding acetamides unless
specified. A series of α-alkyl-α-ethyl glycine ethyl esters were coupled with Ph IOTf smoothly to
2
give the 1º γ-C-H arylation products (3a-3h and 2i). Linear, branched and cyclic alkyl groups
were all compatible with the reaction conditions. Functional groups such as γ-aryl (3f),
ethoxycarbonyl (3g) and methoxyl (3h) groups were tolerated. Although the phthalimido group
was also compatible to the conditions, partial degradation led to only 33% yield of the product
(
2i). However, α-amino esters having phenyl groups at the α- and β-positions underwent ortho-
2
3
C(sp )-H rather than γ-C(sp )-H arylation to give 3j and 3k in 33 % and 65% yield respectively.
Furthermore, substrates derived from L-valine and L-isoleucine were also tested. The α-
methylated valine ethyl ester was mono-arylated at 1º γ-C-H bonds to furnish 2m in 48% yield,
while the α-methylated isoleucine ethyl ester yielded the 1º γ-C-H arylated amino ester 2n in 62%
yield. It needs to be mentioned that the α-tertiary carbon center is required for the method,
because the reaction of 2o did not give any C-H arylation product, but left the starting material
mainly recovered.
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Scheme 3. Scope of α-amino esters
NH2
H
NHP Ph
Standard conditionsa
EtO C
+ Ph IOTf
EtO2C
R3
2
R1 2R3
R
2
R1
R2
1a-1o
2 (P = H); 3 (P = Ac)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
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3
3
3
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0
NHAc
NHAc
NHAc
EtO C
EtO C
2
Ph
2
Ph
EtO C
2
Ph
Ph
4
3b, 68%
3
a, 72% (64%)b
3c, 69%
(mono:di = 2.8:1)
NHAc
NHAc
NHAc
EtO C
EtO C
2
Ph
2
Ph
Ph
EtO C
2
Ph
Ph
Ph
3f, 46%
NH2
3
e, 52% (37%)b
3d, 51%
NHAc
NHAc
EtO C
EtO C
EtO2C
2
2
Ph
OMe
NPhth
CO Et
2
2
2
2i, 29%c
3g, 63%
3h, 57%
NHAc
NHAc
NHAc
EtO C
H
2
H
EtO C
EtO C
2
2
Ph
Ph
Ph
3j, 33%
3k, 65%
NH2 Ph
3l, 54%
NH2 Ph
NH2
EtO C
EtO C
2
2
EtO C
2
Ph
2m, 48%c
2n, 62%c
2o, n.d.
a
Standard conditions: 1 (0.2 mmol), Ph IOTf (0.3 mmol), Pd(OAc) (10 mol%), Ag O (0.75
2
2
2
equiv), HFIP/AcOH (85/15, 0.1 M), air, 100 C, 24 h; conditions for acetylation: AcCl (1.5
b
c
equiv), Et N (2.0 equiv), CH Cl , rt, 15 min. 1.0 mmol scale reactions. The products were
3
2
2
isolated without acetylation.
Table 2. Scope of diaryliodonium salts
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NH2
H
NHAc
Standard conditionsa
EtO C
Ar1
EtO C
2
1
2
2
Ar Ar IOTf
1a
3a, 3p-3y
Entry
Diaryliodonium triflate (4)
Product (3)
NHAc
I
X
X
EtO2C
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OTf
X
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4a, X = H
3a, 72%
3p, 54%
3q, 62%
3r, 74%
3s, 58%
3t, 57%
3u, 67%
3v, 68%
3w, 64%
3x, 41%b
4b, X = p-OMe
4c, X = p-tBu
4d, X = p-Me
4e, X = p-CF3
4f, X = p-F
4g, X = p-Cl
4h, X = p-Br
4i, X = p-CO Me
2
10
4j, X = m-CN
I
X
OTf
1
1
2
4k, X = H
3a, 34%
3y, 31%
1
4l, X = p-NO2
I
OTf
4m
NO2
13
3a (36%)+3y (30%)
a
1
2
Conditions: 1 (0.2 mmol), Ar Ar IOTf (0.3 mmol), Pd(OAc) (10 mol%), Ag O (0.75 equiv),
2
2
HFIP/AcOH (85/15, 0.1 M), air, 100 C, 24 h; conditions for acetylation: AcCl (1.5 equiv), Et N
2.0 equiv), CH Cl , rt, 15 min. 2.0 equiv 4j, 120 ºC.
3
b
(
2
2
Then, the scope of diaryliodonium triflates was investigated (Table 2). A series of symmetric
diaryliodonium triflates were submitted to the reaction with 1a under the above standard
conditions (Entries 1-10, Table 2). Both electron-rich and electron-poor aryl groups were
successfully installed to the γ-carbon of 1a. The tolerated functional groups included methoxyl
(4b), alkyl (4c and 4d), trifluoromethyl (4e), halides (4f, 4g and 4h), methoxycarbonyl (4i) and
cyano (4j) groups. In addition, unsymmetric diaryliodonium salts were also compatible. It was
found that the selectivity was controlled by the steric hindrance rather than the electronic
property of the aryl groups. Therefore, 4k and 4l transferred the smaller Ar groups to afford 3a
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and 3y respectively (Entries 11-12, Table 2). By contrast, the reaction of 4m gave a mixture of
3
a and 3y in 1.2:1 ratio (Entry 13, Table 2).
To better understand the reaction mechanism, we performed several control experiments and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
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KIE study. Firstly, the control experiments among Ag O, AcOH and 1a were set to explore how
2
Ag O worked in the γ-C-H arylation reaction (eq 1, Scheme 4a). Addition of AcOH to the
2
mixture of Ag O (black solid) and HFIP under room temperature led to quick formation of a
2
white precipitate, which was determined as AgOAc by elementary analysis. It became
completely dissolved in HFIP after addition of 2.0 equiv 1a, and precipitated again after further
addition of AcOH to the former solution. The result indicated that AgOAc was in-situ generated
at the beginning of the reaction in a solid state and leached into the organic phase slowly by
interaction with amines, probably forming silver-amine complexes (see SI for details). Secondly,
2
0
the reaction of 1a with Ph IOAc 4n under otherwise the standard conditions was carried out (eq
2
2, Scheme 4a). This reaction gave the product 2a in much lower yield than that with Ph IOTf (27%
2
vs 72%). The result indicated that Ph IOAc was not the key intermediate in the reaction and thus
2
ruled out the possibility that the silver effect was attributed to the transformation of Ph IOTf to
2
Ph IOAc by AgOAc. Thirdly, addition of 0.75 equiv H O to the reaction using 1.5 equiv AgOAc
2
2
led to the decrease of the yield of 2a (eq 3, Scheme 4a). The result suggested that water could not
account for the different activity between Ag O and AgOAc in the reaction.
2
The study of kinetic isotope effects was also carried out to investigate the feature of the C-H
cleavage step. First of all, the reaction of deuterated amino ester 1a-d with Ph IOTf under the
5
2
standard conditions gave the product 3a-d in 12% yield (eq 4, Scheme 4b), which was much
4
lower than the yield of 3a from the reaction of 1a (72% yield). And no D/H exchange was
observed in both the recovered starting material and the product, indicating that the C-H
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cleavage step was irreversible. Then, the one-pot competition reaction between 1a and 1a-d was
5
conducted (eq 5, Scheme 4b). The reaction after 6 hours delivered a mixture of 3a and 3a-d in
4
17% total yield and 5:1 ratio. The observation of a primary kinetic isotope effect suggested that
the C-H cleavage step might be the turnover-limiting step.
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Scheme 4. Control experiments and KIE study
a) Control experiments
AcOH
1a (2.0 equiv)
Ag O
AgOAc
Ag(amine) OAc (eq 1)
2
n
99% yield
AcOH
Black
solid
in HFIP
White solid
in HFIP
Solution
NH2
NH2
Standard conditions
EtO C
EtO C
2
2
(eq 2)
Ph IOAc 4n (1.5 equiv)
Ph
2
(no acetylation step)
2a
1a
2
4 h, 27% or 15% (no Ag O)
2
Pd(OAc)2 (10 mol%)
AgOAc (1.5 equiv)
NH2
NH2
H O (0.75 equiv)
HFIP/AcOH (85/15)
2
EtO C
EtO C
2
2
(eq 3)
Ph
1
00 °C, air, 24 h
2a, 30%
1a
Ph IOTf (1.5 equiv)
2
b) KIE study
NHAc Ph
CD2 (eq 4)
NH2
Standard conditions
CD3
EtO C
2
EtO C
C
2
C
Ph IOTf (1.5 equiv)
2
D
2
D
2
1
a-d5
3a-d4
2
4 h, 12% yield
no D/H exchange
no D/H exchange
Standard conditions
1
a
+
1a-d5
(eq 5)
3a
+
3a-d4
Ph IOTf (1.5 equiv)
2
(
1a/1a-d5 = 1:1)
6 h, 17% total yield,
3a/3a-d4 = 5.0
On the basis of the experimental results and literature reports,4c,17,18 a plausible mechanism for
3
the γ-C(sp )-H arylation of α-amino esters was proposed (Figure 1). At the beginning, Ag O
2
reacted with AcOH to generate AgOAc, which leached to the organic phase by formation of
silver-amine complexes A such as Ag(amine) OAc. Then, either 1 or A reacted with Pd(OAc) to
n
2
give a Pd(II)-amine complex B, which underwent a rate-determining and irreversible C-H
cleavage/palladation to furnish an alkyl-Pd(II) complex C. The oxidative addition of Ar IOTf to
2
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C followed by anion exchange with AgOAc afforded the Pd(IV) complex D, which went through
reductive elimination to produce the arylation product 2.
amine (1)
AcOH
Ag O
2
AgOAc
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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4
4
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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
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2
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Ag(amine) OAc
n
Pd(OAc)2
A
2
1
AgOAc
H C
3
Ar
H C
O
N
3
O
CH3
CH3
O
O
O
Pd
O
O
H
H
Pd
O
H
N
H
H
EtO C
R
D
2
EtO C
R
2
B
RDS
OH
ArI
AgOTf
H C
3
O
O
O
H
H
Ar IOTf
AgOAc
2
Pd
N
EtO C
R
2
C
Figure 1. Plausible mechanism
3. CONCLUSION
3
In conclusion, an efficient NH -directed γ-(sp )-H arylation of α-amino esters with
2
diaryliodonium triflates has been developed by palladium catalysis. The study showed that both
Ag O and the HFIP/AcOH co-solvent system were crucial to the reaction. Using this novel
2
method, aryl groups with various functional groups were successfully installed to a wide range of
α-amino esters, delivering synthetic useful γ-aryl-α-amino esters. Although limitation in the
substrate scope still exists and the reaction mechanism remains unclear, this work is the first
3
example on the NH -directed γ-(sp )-H arylation of functionalized aliphatic amines and might
2
find application in the synthesis of unnatural amino acids, peptides, and natural products. Further
study on exploring reaction mechanism is underway.
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4
. EXPERIMENTAL SECTION
General information. Solvents, starting materials, catalysts were purchased from Chemical
companies and used without further purification. Chromatographic purification was conducted
with technical grade solvents (petroleum ether, dichloromethane and ethyl acetate) and silica gel
0
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2
3
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2
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4
5
6
7
8
9
0
4
0-63 μm. TLC was performed on silica gel 60 F254 TLC glass plates and visualized with UV
1
13
light (254 nm). H and C NMR spectra were recorded on a 400 MHz spectrometer. Chemical
1
shifts were referenced relative to residual solvent signal (CDCl : 7.26 ppm for H NMR, 77.16
3
1
3
1
13
ppm for C NMR; DMSO-d : 2.50 ppm for H NMR, 39.52 ppm for C NMR; CD OD: 4.87
6
3
1
13
1
ppm for H NMR, 49.0 ppm for C NMR; D O: 4.79 ppm for H NMR). Infrared spectra were
2
recorded on a Brucker Alpha-FTIR, which could be used to obtain FTIR transmission spectra in
-1
-1
the range of 500-4000 cm and were reported as cm (w = weak, m = medium, s = strong).
HRMS were performed on a mass spectrometer (ESI) with a Q-TOF analyzer. Melting points
were measured with micro melting point apparatus.
α-Amino esters 1 were prepared from commercial amino acids and alkyl iodides or bromides
by a four-step method according to the reported procedure.15b
Ethyl 2-amino-2-methylbutanoate (1a) was prepared from L-2-aminobutanoic acid (10
1
mmol) and methyl iodide (681 mg, 47% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 4.14
3
(q, J = 7.0 Hz, 2H), 1.83 – 1.67 (m, 1H), 1.67 – 1.48 (m, 3H), 1.37 – 1.14 (m, 6H), 0.84 (t, J =
1
3
1
7.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 177.8, 61.0, 58.1, 34.0, 26.0, 14.4, 8.6. IR
3
(neat) 2955 (m), 2923 (s), 2851 (w), 1742 (w), 1462 (w), 1377 (w), 1189 (w). HRMS (ESI) calcd
+
+
for C H NO [M+H] 146.1176; found 146.1174.
7
16
2
Ethyl 2-amino-2-ethylbutanoate (1b) was prepared from L-2-aminobutanoic acid (10 mmol)
1
and ethyl iodide (858 mg, 54% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 4.17 (q, J =
3
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.0 Hz, 2H), 1.94 – 1.61 (m, 4H), 1.61 – 1.43 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 0.85 (t, J = 7.4
1
3
1
Hz, 6H). C{ H} NMR (101 MHz, CDCl ) δ 177.3, 61.9, 60.9, 32.7, 14.5, 8.4. IR (neat) 2965
3
(w), 2931 (w), 1727 (s), 1456 (w), 1377 (w), 1226 (m), 1142 (w), 1026 (w), 702 (w). HRMS
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
+
+
(ESI) calcd for C H NO [M+H] 160.1332; found 160.1329.
8 18 2
Ethyl 2-amino-2-ethyloctanoate (1c) was prepared from L-2-aminobutanoic acid (10 mmol)
1
and hexyl iodide (992 mg, 46% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 4.16 (q, J =
3
7
1
2
.0 Hz, 2H), 1.92 – 1.65 (m, 2H), 1.65 – 1.40 (m, 4H), 1.40 – 1.18 (m, 10H), 1.18 – 1.01 (m,
1
3
1
H), 1.01 – 0.76 (m, 6H). C{ H} NMR (101 MHz, CDCl ) δ 177.4, 61.5, 60.9, 39.9, 33.0, 31.7,
3
9.7, 24.0, 22.7, 14.5, 14.1, 8.3. IR (neat) 2959 (w), 2927 (s), 2857 (w), 1731 (s), 1462 (m), 1379
+
+
(w), 1187 (s), 1028 (w). HRMS (ESI) calcd for C H NO [M+H] 216.1958; found 216.1956.
1
2
26
2
Ethyl 2-amino-2-ethyl-4-methylpentanoate (1d) was prepared from L-leucine (10 mmol)
1
and ethyl iodide (1.14 g, 61% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 4.42 – 3.93
3
(m, 2H), 1.87 – 1.67 (m, 3H), 1.63 (brs, 2H), 1.56 – 1.41 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.93
13
1
(d, J = 5.2 Hz, 3H), 0.87 – 0.74 (m, 6H). C{ H} NMR (101 MHz, CDCl ) δ 178.0, 61.0, 48.5,
3
3
4.5, 24.9, 24.4, 23.0, 14.4, 8.1. IR (neat) 2957 (s), 2925 (s), 1729 (s), 1456 (m), 1377 (w), 1218
+
+
(w), 1140 (w), 1026 (w), 700 (w). HRMS (ESI) calcd for C H NO [M+H] 188.1645; found
10 22 2
1
88.1643.
Ethyl 2-amino-2-cyclohexylbutanoate (1e) was prepared from L-2-aminobutanoic acid (10
1
mmol) and cyclohexyl iodide (1.15 g, 54% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ
3
4.16 (q, J = 6.9 Hz, 2H), 1.89 – 1.68 (m, 4H), 1.68 – 1.54 (m, 3H), 1.54 – 1.34 (m, 3H), 1.27 (t, J
13
1
=
7.1 Hz, 3H), 1.24 – 0.97 (m, 5H), 0.82 (t, J = 7.3 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ
3
1
77.3, 64.7, 60.8, 45.8, 30.4, 28.1, 26.7, 26.7, 26.6, 26.3, 14.5, 8.6. IR (neat) 2963 (w), 2929 (s),
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
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5
5
5
5
5
5
5
6
2
853 (w), 1729 (s), 1450 (m), 1381 (w), 1213 (m), 1171 (w), 1028 (w). HRMS (ESI) calcd for
+
+
C H NO [M+H] 214.1802; found 214.1798.
1
2
24
2
Ethyl 2-amino-2-ethyl-4-phenylbutanoate (1f) was prepared from L-2-aminobutanoic acid
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
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3
4
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1
(10 mmol) and (2-bromoethyl)benzene (891 mg, 38% yield). Colorless oil. H NMR (400 MHz,
CDCl ) δ 7.31 – 7.23 (m, 2H), 7.23 – 7.13 (m, 3H), 4.19 (q, J = 6.8 Hz, 2H), 2.81 – 2.59 (m,
3
1
H), 2.58 – 2.30 (m, 1H), 2.21 – 1.94 (m, 1H), 1.94 – 1.75 (m, 2H), 1.75 – 1.52 (m, 3H), 1.30 (t,
1
3
1
J = 6.9 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 177.1, 142.0,
3
1
28.6, 128.5, 126.1, 61.5, 61.1, 41.9, 33.1, 30.7, 14.5, 8.3. IR (neat) 2965 (w), 1727 (s), 1454
+
+
(w), 1183 (s), 1030 (w), 700 (w). HRMS (ESI) calcd for C H NO [M+H] 236.1645; found
14 22 2
236.1642.
Diethyl 2-amino-2-ethylsuccinate (1g) was prepared from L-2-aminobutanoic acid (10 mmol)
1
and ethyl 2-bromoacetate (937 mg, 43% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 4.29
3
– 3.94 (m, 4H), 2.94 (d, J = 16.6 Hz, 1H), 2.50 (d, J = 16.6 Hz, 1H), 1.92 (brs, 2H), 1.77 – 1.54
13
1
(m, 2H), 1.38 – 1.10 (m, 6H), 0.88 (t, J = 7.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ
3
1
76.4, 171.7, 61.3, 60.7, 59.4, 43.3, 33.3, 14.34, 14.28, 8.0. IR (neat) 2980 (w), 1734 (s), 1375
+
+
(w), 1185 (s), 1030 (m). HRMS (ESI) calcd for C H NO [M+H] 218.1387; found 218.1382.
10 20 4
Ethyl 2-amino-2-ethyl-5-methoxypentanoate (1h) was prepared from L-2-aminobutanoic
1
acid (10 mmol) and 1-bromo-3-methoxypropane (1.38 g, 68% yield). Colorless oil. H NMR
(400 MHz, CDCl ) δ 4.16 (q, J = 7.0 Hz, 2H), 3.38 – 3.33 (m, 2H), 3.30 (s, 3H), 1.89 – 1.71 (m,
3
3H), 1.65 (brs, 2H), 1.61 – 1.51 (m, 2H), 1.51 – 1.38 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H), 0.85 (t, J
13
1
=
7.3 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 177.1, 72.9, 61.2, 61.0, 58.6, 36.4, 33.0,
3
2
4.3, 14.5, 8.3. IR (neat) 3414 (s), 2967 (m), 2933 (m), 2361 (s), 2341 (s), 1729 (s), 1119 (s).
+
+
HRMS (ESI) calcd for C H NO [M+H] 204.1594; found 204.1594.
1
0
22
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Ethyl 2-amino-5-(1,3-dioxoisoindolin-2-yl)-2-ethylpentanoate (1i) was prepared from L-2-
aminobutanoic acid (10 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione (1.42 g, 45% yield).
1
Colorless oil. H NMR (400 MHz, CDCl ) δ 7.89 – 7.78 (m, 2H), 7.75 – 7.63 (m, 2H), 4.13 (q, J
3
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
=
6.5 Hz, 2H), 3.94 – 3.37 (m, 2H), 1.86 – 1.66 (m, 3H), 1.62 (s, 2H), 1.59 – 1.45 (m, 3H), 1.22
1
3
1
(
t, J = 6.6 Hz, 3H), 0.82 (t, J = 7.0 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 176.8, 168.4,
3
1
2
34.0, 132.2, 123.3, 61.2, 61.1, 38.2, 36.9, 32.9, 23.5, 14.4, 8.3. IR (neat) 3468 (s), 3414 (s),
969 (w), 2361 (w), 1714 (s), 1617 (w), 1397 (m), 1218 (w), 721 (w). HRMS (ESI) calcd for
+
+
C H N O [M+H] 319.1652; found 319.1653.
1
7
23
2
4
Ethyl 2-amino-2-benzylbutanoate (1j) was prepared from L-2-aminobutanoic acid (10 mmol)
1
and benzyl bromide (1.52 g, 69% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 7.40 – 7.19
3
(
m, 3H), 7.16 (d, J = 7.0 Hz, 2H), 4.39 – 4.00 (m, 2H), 3.18 (d, J = 13.2 Hz, 1H), 2.76 (d, J =
1
3.2 Hz, 1H), 2.12 – 1.84 (m, 1H), 1.83 – 1.41 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.3
1
3
1
Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 176.6, 136.7, 130.1, 128.5, 127.0, 62.5, 61.1, 45.9,
3
3
1
3.4, 14.4, 8.5. IR (neat) 2967 (w), 2933 (w), 1729 (s), 1454 (w), 1379 (w), 1187 (s), 1111 (w),
+
+
028 (w), 702 (w). HRMS (ESI) calcd for C H NO [M+H] 222.1489; found 222.1485.
1
3
20
2
Ethyl 2-amino-2-phenylbutanoate (1k) was prepared from L-2-phenylglycine (10 mmol) and
1
ethyl iodide (1.15 g, 56% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 7.51 (d, J = 7.8
3
Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.30 – 7.21 (m, 1H), 4.27 – 4.06 (m, 2H), 2.32 – 2.11 (m, 1H),
1
3
1
2
.11 – 1.96 (m, 1H), 1.90 (brs, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). C{ H}
NMR (101 MHz, CDCl ) δ 175.8, 143.4, 128.4, 127.4, 125.7, 64.2, 61.5, 32.9, 14.2, 8.6. IR
3
(
neat) 2976 (w), 2937 (w), 1727 (s), 1601 (w), 1495 (w), 1448 (w), 1366 (w), 1224 (s), 1028 (w),
+
+
7
63 (w), 700 (w). HRMS (ESI) calcd for C H NO [M+H] 208.1332; found 208.1331.
12 18 2
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Ethyl 2-amino-2-phenylpropanoate (1l) was prepared from L-2-phenylglycine (10 mmol)
1
and methyl iodide (981 mg, 51% yield). Colorless oil. H NMR (400 MHz, CDCl ) δ 7.48 (d, J =
3
7.7 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.30 – 7.19 (m, 1H), 4.17 (q, J = 7.0 Hz, 2H), 1.95 (brs,
0
1
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7
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0
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6
7
8
9
0
13
1
2
1
1
H), 1.69 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 176.3, 144.4,
3
28.5, 127.5, 125.2, 61.5, 60.7, 27.6, 14.2. IR (neat) 2978 (w), 2927 (w), 1725 (s), 1601 (w),
+
446 (w), 1373 (w), 1234 (m), 1095 (w), 1028 (w), 700 (w). HRMS (ESI) calcd for C H NO
11 16
2
+
[
M+H] 194.1176; found 194.1174.
Ethyl 2-amino-2,3-dimethylbutanoate (1m) was prepared from L-valine (10 mmol) and
1
methyl iodide. 911 mg, 57% yield. Colorless oil. H NMR (400 MHz, CDCl ) δ 4.16 (q, J = 7.1
3
Hz, 2H), 2.09 – 1.84 (m, 1H), 1.43 (brs, 2H), 1.31 – 1.21 (m, 6H), 0.91 (d, J = 6.8 Hz, 3H), 0.86
13
1
(
d, J = 6.9 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 178.0, 60.9, 60.7, 35.8, 23.7, 17.5, 16.5,
3
1
4.4. IR (neat) 3475 (s), 3415 (s), 2361 (s), 1618 (w), 1384 (w). HRMS (ESI) calcd for
+
+
C H NO [M+H] 160.1332; found 160.1328.
8
18
2
Ethyl 2-amino-2,3-dimethylpentanoate (1n) was prepared from L-isoleucine (10 mmol) and
1
methyl iodide (605 mg, 35% yield, dr 1:1). Colorless oil. H NMR (400 MHz, CDCl ) δ 4.15 (q,
3
J = 7.0 Hz, 2H), 1.73 – 1.59 (m, 1H), 1.58 – 1.33 (m, 3H), 1.33 – 1.18 (m, 6H), 1.10 – 0.95 (m,
1
3
1
1
H), 0.95 – 0.81 (m, 6H). C{ H} NMR (101 MHz, CDCl ) δ 178.3, 178.0, 61.2, 61.1, 60.9,
3
4
2.9, 42.8, 24.6, 23.8, 23.5, 23.4, 14.4, 13.6, 12.8, 12.7. IR (neat) 3416 (s), 2967 (s), 2361 (s),
+
+
1
730 (s), 1618 (w), 1457 (w), 1384 (w), 1232 (w). HRMS (ESI) calcd for C H NO [M+H]
9 20 2
174.1489; found 174.1488.
Diaryliodonium salts 4a-4n were prepared according to the reported procedures.20-23
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Diphenyliodonium triflate (4a) was synthesized from benzene (61.5 mmol) and iodine (15
1
mmol) in 81% yield (10.5g, 24.8 mmol). H NMR (400 MHz, DMSO-d ) δ 8.36 – 8.18 (m, 4H),
6
7.66 (t, 2H), 7.54 (t, 4H). The data matched with that in the literature report.21
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Bis(4-methoxyphenyl)iodonium triflate (4b) was synthesized from 4-iodoanisole (5.0 mmol)
1
and 4-methoxyphenylboronic acid (5.0 mmol) in 45% yield (1.1 g, 2.25 mmol). H NMR (400
MHz, CDCl ) δ 7.89 (d, J = 9.9 Hz, 4H), 6.93 (d, J = 12.1 Hz, 4H), 3.82 (s, 6H). The NMR data
3
matched with literature report.22
Bis(4-(tert-butyl)phenyl)iodonium triflate (4c) was synthesized from tert-butylbenzene (10
1
mmol) and iodine (2.5 mmol) in 82% yield (2.2 g, 4.06 mmol). H NMR (400 MHz, CDCl ) δ
3
7.89 (d, J = 8.1 Hz, 4H), 7.46 (d, 4H), 1.29 (s, 18H). The data matched with that in the literature
report. 21
Di-p-tolyliodonium triflate (4d) was synthesized from 4-iodotoluene (5.0 mmol) and p-
1
tolylboronic acid (5.5 mmol) in 57% yield (1.3 g, 2.84 mmol). H NMR (400 MHz, CD OD) δ
3
8
.89 (d, J = 7.7 Hz, 4H), 8.13 (d, J = 7.7 Hz, 4H), 3.14 (s, 6H). The data matched with that in the
literature report.22
Bis(4-(trifluoromethyl)phenyl)iodonium triflate (4e) was synthesized from 4-
trifluoromethylphenyl iodide (5.0 mmol) and 4-trifluoromethylphenyl boronic acid (5.5 mmol) in
1
7
2% yield (2.04 g, 3.6 mmol). H NMR (400 MHz, CDCl ) δ 8.15 (d, J = 8.3 Hz, 4H), 7.73 (d, J
3
=
8.3 Hz, 4H). The data matched with that in the literature report.22
Bis(4-fluorophenyl)iodonium triflate (4f) was synthesized from 4-fluorobenzene (10 mmol)
1
and iodine (2.5 mmol) in 78% yield (1.82 g, 3.9 mmol). H NMR (400 MHz, CD OD) δ 8.37 –
3
8
.17 (m, 4H), 7.42 – 7.21 (m, 4H). The data matched with that in the literature report.21
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Bis(4-chlorophenyl)iodonium triflate (4g) was synthesized from 1-chloro-4-iodobenzene
1
(
5.0 mmol) and chlorobenzene (5.5 mmol) in 84% yield (2.09 g, 4.2 mmol). H NMR (400 MHz,
DMSO-d ) δ 8.25 (d, J = 7.9 Hz, 4H), 7.65 (d, J = 13.6 Hz, 4H). The data matched with that in
6
0
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the literature report.22
Bis(4-bromophenyl)iodonium triflate (4h) was synthesized from 1-bromo-4-iodobenzene
1
(
5.0 mmol) and bromobenzene (5.5 mmol) in 74% yield (2.17 g, 3.7 mmol). H NMR (400 MHz,
DMSO-d ) δ 8.15 (d, J = 14.1 Hz, 4H), 7.76 (d, J = 7.6 Hz, 4H). The data matched with literature
6
report.22
Bis(4-(methoxycarbonyl)phenyl)iodonium triflate (4i) was synthesized from 4-
methoxycarbonylphenyl iodide (5.0 mmol) and 4-methoxycarbonyl phenyl boronic acid (5.5
1
mmol) in 62% yield (1.69 g, 3.1 mmol). H NMR (400 MHz, CDCl ) δ 8.20 – 7.92 (m, 8H), 3.91
3
(
s, 6H). The NMR data matched with literature report.22
Bis(3-cyanophenyl)iodonium triflate (4j) 22 was synthesized from 3-cyanophenyl iodide (5.0
mmol) and 3-cyanophenyl boronic acid (5.5 mmol) in 84% yield (white solid, 2.02 g, 4.2 mmol).
1
H NMR (400 MHz, DMSO-d ) δ 8.90 (s, 2H), 8.63 (d, J = 7.8 Hz, 2H), 8.21 (d, J = 6.6 Hz, 2H),
6
1
3
1
7
1
1
3
.80 (t, J = 7.1 Hz, 2H). C{ H} NMR (101 MHz, DMSO) δ 139.8, 138.6, 136.0, 132.6, 116.92,
16.90, 114.0. IR (neat) 3415 (s), 3081 (m), 3020 (m), 2361 (m), 2235 (s), 1617 (m), 1554 (w),
+
+
471 (w), 1412 (w), 1274 (s), 1172 (s), 801 (m). HRMS (ESI) calcd for C H IN [M-TfO]
1
4
8
2
30.9727; found 330.9723. mp. 218-220 °C.
Mesityl(phenyl)iodonium triflate (4k) was synthesized from phenyl iodide (5.0 mmol) and
1
mesitylene (5.5 mmol) in 72% yield (1.70 g, 3.6 mmol). H NMR (400 MHz, CDCl ) δ 7.68 (d,
3
J = 7.9 Hz, 2H), 7.60 – 7.48 (m, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.11 (s, 2H), 2.62 (s, 6H), 2.36 (s,
3H). The NMR data matched with literature report.23
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Mesityl(4-nitrophenyl)iodonium triflate (4l) was synthesized from 4-nitroiodobenzene (5.0
1
mmol) and mesitylene (5.5 mmol) in 30% yield (0.78 g, 1.5 mmol). H NMR (400 MHz, DMSO-
d6) δ 8.25 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.6 Hz, 2H), 7.25 (s, 2H), 2.59 (s, 6H), 2.31 (s, 3H).
1
1
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2
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The NMR data matched with literature report. 21
(4-Nitrophenyl)(phenyl)iodonium triflate (4m) was synthesized from 4-nitroiodobenzene
1
(
5.0 mmol) and benzene (5.5 mmol) in 80% yield (1.9 g, 4.0 mmol). H NMR (400 MHz,
DMSO-d ) δ 8.48 (d, J = 9.0 Hz, 2H), 8.40 – 8.25 (m, 4H), 7.70 (t, J = 7.4 Hz, 1H), 7.56 (t, J =
6
7
.7 Hz, 2H). The NMR data matched with literature report.23
Diphenyliodonium acetate (4n) was synthesized from 4a (4 mmol) by two-step anion
1
exchange in 88% yield (two steps, 1.2 g). H NMR (400 MHz, CDCl ) δ 7.89 (d, J = 7.6 Hz,
3
4
H), 7.51 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.7 Hz, 4H), 1.92 (s, 3H). The NMR data matched with
literature report.20
3
General procedure for the γ-C(sp )-H arylation of α-amino esters. A mixture of Pd(OAc)2
(
4.5 mg, 0.02 mmol, 0.1 equiv), Ag O (34.8 mg, 0.15 mmol, 0.75 equiv), α-amino ester 1 (0.2
2
mmol, 1.0 equiv), diaryliodonium triflate (0.3 mmol, 1.5 equiv) and HFIP/AcOH (85/15, 2 mL)
was stirred at room temperature for 20 min and heated at 100 ºC under air atmosphere for 24 h.
After concentration, the residue was treated with Et O (10 mL) and aq. HCl (1.0 M, 10 mL) and
2
then filtered. The organic layer was extracted with hydrochloric acid (1.0 M, 3 × 5 mL). The
combined aqueous phase was basified (pH = 12) with 5 M aqueous NaOH solution and extracted
with CH Cl (3 × 10 mL). The combined organic extracts were dried over Na SO , filtered and
2
2
2
4
concentrated under reduced pressure. For some cases, the residue was purified by flash
chromatography (silica gel) with a mixture of CH Cl /MeOH (90/10) containing 0.1% of aq.
2
2
ammonia (25-28%) as the eluent to give 2. For other cases, the residue was treated with
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dichloromethane (5 mL), Et N (42 µL, 0.3 mmol, 1.5 equiv) and acetyl chloride (17 µL, 0.24
3
mmol, 1.2 eq.). After being stirred at room temperature for 15 min, the reaction mixture was
diluted with 5 mL CH Cl and washed with HCl (10 ml, 0.5 M), sat. aq. NaHCO solution (10
2
2
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0
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ml) and brine (10 mL) successively. The organic phase was dried over Na SO , filtered and
2
4
concentrated under reduced pressure. The residue was then purified through flash
chromatography on a silica gel column with CH Cl /MeOH (99/1) as the eluent to give the pure
2
2
product 3.
Ethyl 2-amino-2-methyl-4-phenylbutanoate (2a) was synthesized from a 1.0 mmol scale
reaction of 1a with Ph IOTf 4a according to the general procedure (142.4 mg, 64% yield).
2
1
Colorless oil. H NMR (400 MHz, CDCl ) δ 7.34 – 7.23 (m, 2H), 7.23 – 7.12 (m, 3H), 4.17 (q, J
3
=
7.0 Hz, 2H), 2.67 (td, J = 12.8, 5.2 Hz, 1H), 2.52 (td, J = 12.8, 4.6 Hz, 1H), 2.04 (td, J = 12.8,
1
3
1
4
.6 Hz, 1H), 1.98 – 1.79 (m, 3H), 1.38 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). C{ H} NMR (101
MHz, CDCl ) δ 177.6, 141.8, 128.6, 128.5, 126.1, 61.2, 57.8, 43.0, 30.9, 26.6, 14.4. IR (neat)
3
3
529 (m), 3434 (s), 2970 (s), 1727 (s), 1601 (w), 1453 (w), 1174 (s), 1028 (w), 704 (w). HRMS
+
+
(
ESI) calcd for C H NO [M+H] 222.1489; found 222.1486.
13 20 2
Ethyl 2-acetamido-2-methyl-4-phenylbutanoate (3a) was synthesized from the reaction of
1
8
1
a with Ph IOTf 4a according to the general procedure (37.7 mg, 72% yield). White solid. mp.
2
1
1-83 °C. H NMR (400 MHz, CDCl ) δ 7.24 (t, J = 7.1 Hz, 2H), 7.19 – 7.07 (m, 3H), 6.34 (s,
3
H), 4.33 – 4.02 (m, 2H), 2.82 – 2.64 (m, 1H), 2.65 – 2.47 (m, 1H), 2.44 – 2.24 (m, 1H), 2.19 –
1
3
1
2.01 (m, 1H), 1.94 (s, 3H), 1.62 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). C{ H} NMR (101 MHz,
CDCl ) δ 174.8, 169.3, 141.3, 128.6, 128.5, 126.1, 62.0, 60.6, 37.5, 31.0, 24.2, 23.5, 14.3. IR
3
(neat) 3292 (m), 2984 (w), 2937 (w), 1738 (s), 1656 (s), 1544 (s), 1454 (m), 1375 (w), 1248 (w),
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+
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193 (w), 1122 (w), 1030 (w), 702 (w), HRMS (ESI) calcd for C H NO [M+H] 264.1594;
15 22 3
found 264.1592.
Ethyl 2-acetamido-2-ethyl-4-phenylbutanoate (3b) and Ethyl 2-acetamido-2-phenethyl-4-
1
1
1
1
1
1
1
1
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phenylbutanoate (3f) were synthesized from the reaction of 1b with Ph IOTf 4a according to
2
the general procedure (40.3 mg, 68% yield, 3b/3f = 2.8:1). 3b (mono-arylation product): white
1
solid. mp. 62-64 °C. H NMR (400 MHz, CDCl ) δ 7.31 – 7.21 (m, 2H), 7.21 – 7.07 (m, 3H),
3
6
2
.45 (s, 1H), 4.33 – 4.06 (m, 2H), 3.00 – 2.77 (m, 1H), 2.68 – 2.45 (m, 2H), 2.41 – 2.22 (m, 1H),
.13 – 2.02 (m, 1H), 2.00 (s, 3H), 1.85 – 1.70 (m, 1H), 1.30 (t, J = 7.0 Hz, 3H), 0.75 (t, J = 7.3
1
3
1
Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.3, 169.2, 141.4, 128.6, 128.5, 126.1, 65.6,
3
62.0, 36.6, 31.1, 28.4, 24.3, 14.4, 8.5. IR (neat) 3296 (w), 2976 (w), 2937 (w), 1734 (s), 1658 (s),
1
540 (m), 1454 (m), 1373 (m), 1238 (m), 1189 (m), 1030 (w), 748 (w), 700 (w). HRMS (ESI)
+
+
calcd for C H NO [M+H] 278.1751; found 278.1742. 3f (bis-arylation product): colorless
1
6
24
3
1
oil. H NMR (400 MHz, CDCl ) δ 7.29 – 7.19 (m, 4H), 7.19 – 7.05 (m, 6H), 6.48 (s, 1H), 4.11
3
(
q, J = 7.0 Hz, 2H), 3.05 – 2.79 (m, 2H), 2.71 – 2.45 (m, 2H), 2.45 – 2.22 (m, 2H), 2.13 – 2.00
1
3
1
(
m, 2H), 1.95 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.2, 169.2,
3
1
41.2, 128.6, 128.5, 126.1, 64.8, 62.2, 36.8, 30.9, 24.2, 14.4. IR (neat) 3296 (w), 3027 (w), 2933
(
w), 1731 (s), 1660 (s), 1497 (s), 1454 (w), 1373 (w), 1195 (s), 1030 (w), 751 (w), 700 (s).
+
+
HRMS (ESI) calcd for C H NO [M+H] 354.2064; found 354.2055.
2
2
28
3
Ethyl 2-acetamido-2-phenethyloctanoate (3c) was synthesized from the reaction of 1c with
1
Ph IOTf 4a according to the general procedure (46.2 mg, 69% yield). Colorless oil. H NMR
2
(
400 MHz, CDCl ) δ 7.29 – 7.21 (m, 2H), 7.20 – 7.09 (m, 3H), 6.45 (s, 1H), 4.30 – 4.08 (m, 2H),
3
3
.00 – 2.79 (m, 1H), 2.67 – 2.41 (m, 2H), 2.37 – 2.16 (m, 1H), 2.15 – 2.01 (m, 1H), 1.99 (s, 3H),
1
3
1
1.77 – 1.64 (m, 1H), 1.38 – 1.12 (m, 10H), 1.02 – 0.88 (m, 1H), 0.86 (t, J = 6.0 Hz, 3H). C{ H}
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NMR (101 MHz, CDCl ) δ 174.5, 169.1, 141.4, 128.6, 128.4, 126.0, 65.0, 62.0, 36.7, 35.4, 31.8,
3
3
1.0, 29.1, 24.3, 24.2, 22.7, 14.4, 14.2. IR (neat) 3302 (w), 2955 (w), 2929 (s), 2857 (w), 1734
(s), 1658 (s), 1499 (m), 1454 (m), 1373 (m), 1197 (s), 1028 (w), 748 (w), 700 (w). HRMS (ESI)
0
1
2
3
4
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6
7
8
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0
1
2
3
4
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7
8
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0
1
2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
calcd for C H NO [M+H] 334.2377; found 334.2372.
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32
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Ethyl 2-acetamido-4-methyl-2-phenethylpentanoate (3d) was synthesized from the reaction
of 1d with Ph IOTf 4a according to the general procedure (31.4 mg, 51% yield). Colorless oil.
2
1
H NMR (400 MHz, CDCl ) δ 7.31 – 7.20 (m, 2H), 7.20 – 7.02 (m, 3H), 6.56 (s, 1H), 4.18 (q, J
3
=
7.1 Hz, 2H), 3.04 – 2.80 (m, 1H), 2.67 – 2.45 (m, 2H), 2.35 – 2.14 (m, 1H), 2.09 – 1.88 (m,
4
H), 1.78 – 1.60 (m, 1H), 1.60 – 1.45 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H),
1
3
1
0.77 (d, J = 6.5 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 175.1, 169.1, 141.3, 128.6, 128.4,
3
1
1
26.0, 64.3, 62.0, 43.8, 37.6, 30.7, 24.9, 24.4, 23.9, 22.9, 14.3. IR (neat) 2957 (w), 2935 (w),
729 (s), 1660 (s), 1499 (s), 1454 (w), 1373 (m), 1228 (m), 1187 (s), 1134 (w), 1022 (w), 748
+
+
(w), 700 (w). HRMS (ESI) calcd for C H NO [M+H] 306.2064; found 306.2056.
1
8
28
3
Ethyl 2-acetamido-2-cyclohexyl-4-phenylbutanoate (3e) was synthesized from the reaction
of 1e with Ph IOTf 4a according to the general procedure (For a 0.2 mmol scale reaction: 34.8
2
1
mg, 52% yield; for a 1.0 mmol scale reaction: 122.5 mg). Colorless oil. H NMR (400 MHz,
CDCl ) δ 7.33 – 7.21 (m, 2H), 7.20 – 7.05 (m, 3H), 6.56 (s, 1H), 4.34 – 4.10 (m, 2H), 3.13 – 2.89
3
(m, 1H), 2.69 – 2.47 (m, 1H), 2.38 – 2.12 (m, 3H), 2.05 (s, 3H), 1.85 (d, J = 11.8 Hz, 1H), 1.79-
1
.68 (m, 3H), 1.68 – 1.63 (m, 1H), 1.33 (t, J = 7.0 Hz, 3H), 1.29 – 1.12 (m, 3H), 1.13 – 0.96 (m,
1
3
1
1H), 0.78 (m, 1H). C{ H} NMR (101 MHz, CDCl ) δ 173.7, 168.9, 141.8, 128.7, 128.4, 126.0,
3
6
3
8.2, 61.9, 43.8, 33.7, 31.4, 28.5, 28.1, 26.7 (two carbons overlapped), 26.5, 24.7, 14.5. IR (neat)
310 (w), 2933 (s), 2853 (w), 1729 (s), 1660 (s), 1499 (s), 1452 (w), 1373 (w), 1199 (s), 1028
+
+
(w), 751 (w), 702 (w). HRMS (ESI) calcd for C H NO [M+H] 332.2220; found 332.2211.
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Ethyl 2-acetamido-2-phenethyl-4-phenylbutanoate (3f) was synthesized from the reaction
of 1f with Ph IOTf 4a according to the general procedure (32.3 mg, 46% yield). See the
2
characterization data above for the reaction of 1b with 4a.
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Diethyl 2-acetamido-2-phenethylsuccinate (3g) was synthesized from the reaction of 1g with
1
Ph IOTf 4a according to the general procedure (42.2 mg, 63% yield). Colorless oil. H NMR
2
(
400 MHz, CDCl ) δ 7.32 – 7.22 (m, 2H), 7.22 – 7.05 (m, 3H), 6.65 (s, 1H), 4.39 – 4.16 (m, 2H),
3
4
.09 (q, J = 7.1 Hz, 2H), 3.72 (d, J = 16.4 Hz, 1H), 3.14 – 2.76 (m, 2H), 2.71 – 2.47 (m, 1H),
2
.47 – 2.22 (m, 1H), 2.04 – 1.87 (m, 4H), 1.31 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 172.9, 170.6, 169.6, 140.9, 128.6, 128.5, 126.2, 62.4, 61.7,
3
60.8, 40.1, 36.6, 30.4, 24.2, 14.3 (two carbons overlapped). IR (neat) 2982 (w), 1736 (s), 1678
+
(
w), 1499 (w), 1373 (w), 1193 (s), 1030 (w), 702 (w). HRMS (ESI) calcd for C H NO
18 26 5
+
[
M+H] 336.1805; found 336.1801.
Ethyl 2-acetamido-5-methoxy-2-phenethylpentanoate (3h) was synthesized from the
reaction of 1h with Ph IOTf 4a according to the general procedure (36.4 mg, 57% yield).
2
1
Colorless oil. H NMR (400 MHz, CDCl ) δ 7.26 – 7.20 (m, 2H), 7.20 – 7.05(m, 3H), 6.48 (s,
3
1
2
1
1
H), 4.37 – 4.02 (m, 2H), 3.39 – 3.29 (m, 2H), 3.29 (s, 3H), 2.96 – 2.76(m, 1H), 2.65 – 2.44 (m,
H), 2.41 – 2.22(m, 1H), 2.19 – 2.03(m, 1H), 1.98 (s, 3H), 1.88 – 1.75(m, 1H), 1.71 – 1.62(m,
1
3
1
H), 1.60 – 1.45(m, 1H), 1.29(t, J = 6.9 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.2,
3
69.2, 141.3, 128.6, 128.5, 126.1, 72.5, 64.6, 62.2, 58.6, 36.7, 32.1, 31.0, 24.6, 24.3, 14.4. IR
(neat) 3412 (s), 2931 (m), 2870 (m), 2361 (s), 2341 (m), 1734 (s), 1653 (s), 1455 (w), 1375 (w),
+
+
1
119 (w). HRMS (ESI) calcd for C H NO [M+H] 322.2013; found 322.2015.
18 28 4
Ethyl 2-amino-5-(1,3-dioxoisoindolin-2-yl)-2-phenethylpentanoate (2i) was synthesized
from the reaction of 1i with Ph IOTf 4a according to the general procedure without acetylation
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(
22.8 mg, 29% yield). H NMR (400 MHz, CDCl ) δ 7.90 – 7.77 (m, 2H), 7.77 – 7.64 (m, 2H),
3
7
.34 – 7.21 (m, 2H), 7.21 – 7.07 (m, 3H), 4.15 (q, J = 7.0 Hz, 2H), 3.81 – 3.57 (m, 2H), 2.73 –
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0
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8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
4
H), 1.30 – 1.22(m, 3H). C{ H} NMR (101 MHz, CDCl ) δ 176.1, 168.5, 141.5, 134.1, 132.2,
3
1
28.6, 128.5, 126.1, 123.3, 61.5, 61.1, 41.7, 38.0, 37.0, 30.5, 23.4, 14.4. HRMS (ESI) calcd for
+
+
C H N O [M+H] 395.1965; found 395.1966.
23 27
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4
Ethyl 2-([1,1'-biphenyl]-2-ylmethyl)-2-acetamidobutanoate (3j) was synthesized from the
reaction of 1j with Ph IOTf 4a according to the general procedure (22.3 mg, 33% yield).
2
1
Colorless oil. H NMR (400 MHz, CDCl ) δ 7.45 – 7.38 (m, 2H), 7.38 – 7.29 (m, 3H), 7.28 –
3
7.22 (m, 3H), 7.20 – 7.15 (m, 1H), 5.99 (s, 1H), 4.00 (dq, J = 10.8, 7.1 Hz, 1H), 3.76 (d, J = 14.4
Hz, 1H), 3.66 (dq, J = 10.8, 7.2 Hz, 1H), 3.37 (d, J = 14.4 Hz, 1H), 2.41 (td, J = 14.7, 7.4 Hz,
1
H), 1.88 (s, 3H), 1.71 (td, J = 14.5, 7.3 Hz, 1H), 1.04 (t, J = 7.1 Hz, 3H), 0.54 (t, J = 7.4 Hz,
1
3
1
3H). C{ H} NMR (101 MHz, CDCl ) δ 173.3, 169.3, 142.8, 142.0, 134.0, 131.1, 131.0, 129.8,
3
1
2
28.5, 128.4, 127.0, 126.9, 65.6, 61.8, 36.9, 28.6, 24.3, 14.0, 8.2. IR (neat) 3288 (w), 2978 (w),
937 (w), 1734 (s), 1658 (s), 1511 (w), 1446 (w), 1371 (w), 1226 (m), 1030 (w), 753 (s), 706 (s).
+
+
HRMS (ESI) calcd for C H NO [M+H] 340.1907; found 340.1900.
21 26
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Ethyl 2-([1,1'-biphenyl]-2-yl)-2-acetamidobutanoate (3k) was synthesized from the reaction
of 1k with Ph IOTf 4a according to the general procedure (42.6 mg, 65% yield). Colorless oil.
2
1
H NMR (400 MHz, CDCl ) δ 7.70 (d, J = 8.0 Hz, 1H), 7.35 – 7.17 (m, 5H), 7.17 – 7.08 (m,
3
1H), 6.96 (d, J = 7.5 Hz, 1H), 6.93 – 6.84 (m, 1H), 6.21 (s, 1H), 4.15 – 3.94 (m, 1H), 3.94 – 3.70
(
m, 1H), 3.20 – 2.88 (m, 1H), 2.37 – 2.05 (m, 1H), 1.68 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H), 0.65 (t,
1
3
1
J = 7.2 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 172.8, 167.9, 142.3, 141.3, 137.7, 131.7,
3
129.7, 129.4, 128.2, 127.7, 127.4, 127.3, 77.5, 62.2, 27.4, 24.1, 14.1, 8.3. IR (neat) 3412 (w),
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978 (w), 2935 (w), 1731 (s), 1681 (s), 1499 (s), 1368 (w), 1236 (m), 1146 (w), 1024 (w), 753
+
+
(m), 706 (m). HRMS (ESI) calcd for C H NO [M+H] 326.1751; found 326.1742.
20 24 3
Ethyl 2-([1,1'-biphenyl]-2-yl)-2-acetamidopropanoate (3l) was synthesized from the
1
1
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1
1
1
1
1
1
2
2
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2
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2
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reaction of 1l with Ph IOTf 4a according to the general procedure (33.4 mg, 54% yield).
2
1
Colorless oil. H NMR (400 MHz, CDCl ) δ 7.72 (d, J = 8.0 Hz, 1H), 7.49 – 7.25 (m, 5H), 7.25
3
–
4
7.10 (m, 1H), 7.07 (d, J = 10.9 Hz, 1H), 7.03 – 6.90 (m, 1H), 6.39 (s, 1H), 4.35 – 4.05 (m, 1H),
1
3
1
.05 – 3.85 (m, 1H), 2.02 (s, 3H), 1.74 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). C{ H} NMR (101
MHz, CDCl ) δ 174.3, 168.0, 142.2, 140.9, 137.3, 131.5, 129.7, 129.2, 128.4, 127.6, 127.4,
3
1
27.3, 62.3, 61.7, 24.4, 24.1, 13.9. IR (neat) 3412 (w), 2984 (w), 2929 (w), 1731 (s), 1683 (s),
1499 (s), 1446 (w), 1371 (w), 1287 (s), 1244 (s), 1146 (w), 1022 (w), 757 (m), 706 (m). HRMS
+
+
(ESI) calcd for C H NO [M+H] 312.1594; found 312.1590.
19 22 3
Ethyl 2-amino-2,3-dimethyl-4-phenylbutanoate (2m) was synthesized from the reaction of
1m with Ph IOTf 4a according to the general procedure without acetylation (28.2 mg, 48%
2
1
yield, dr 1.2:1) Colorless oil. H NMR (400 MHz, CDCl ) major isomer: δ 7.29 – 7.22 (m, 2H),
3
,
7
1
7
.22 – 7.13 (m, 3H), 4.23 (q, J = 7.1, Hz, 2H), 2.84 (d, J = 11.4 Hz, 1H), 2.52 – 2.12 (m, 2H),
.50 (s, 3H), 1.42 – 1.17 (m, 3H), 0.90 (d, J = 6.7 Hz, 3H). minor isomer: δ 7.29 – 7.22 (m, 2H),
.22 – 7.13 (m, 3H), 4.23 (q, J = 7.1, 2H), 3.07 (d, J = 12.3 Hz, 1H), 2.52 – 2.12 (m, 2H), 1.57
1
3
1
(s, 3H), 1.42 – 1.17 (m, 3H), 0.84 (d, J = 6.6 Hz, 3H). C{ H} NMR (101 MHz, CDCl two
3,
diasteriomers) δ 175.5, 175.1, 140.6, 129.32, 129.27, 128.4, 126.09, 126.05, 62.1, 62.0, 61.6,
42.7, 38.2, 37.1, 22.9, 22.7, 14.4, 14.3, 13.9, 12.9. IR (neat) 3414 (s), 2976 (s), 2933 (s), 2362
(w), 1729 (s), 1524 (w), 1455 (w), 1384 (w), 1207 (m), 1024 (w). HRMS (ESI) calcd for
+
+
C H NO [M+H] 236.1645; found 236.1644.
1
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Ethyl 2-amino-3-benzyl-2-methylpentanoate (2n) was synthesized from the reaction of 1n
with Ph IOTf 4a according to the general procedure without acetylation (30.7 mg, 62% yield, dr
2
1
1.1:1). Colorless oil. H NMR (400 MHz, CDCl ) major isomer: δ 7.31 – 7.22 (m, 3H), 7.22 –
3
0
1
2
3
4
5
6
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0
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7
.13 (m, 2H), 4.40 – 3.80 (m, 2H), 2.74 (dd, J = 13.9, 4.2 Hz, 1H), 2.58 – 2.32 (m, 1H), 2.16 –
.87 (m, 1H), 1.77 – 1.47 (m, 2H), 1.31 (s, 3H), 1.28 – 1.19 (m, 3H), 0.76 (t, J = 7.5 Hz, 3H).
1
minor isomer: δ 7.31 – 7.22 (m, 3H), 7.22 – 7.13 (m, 2H), 4.40 – 3.80 (m, 2H), 2.89 (dd, J =
1
1
4.2, 4.5 Hz, 1H), 2.58 – 2.32 (m, 1H), 2.16 – 1.87 (m, 1H), 1.77 – 1.47 (m, 2H), 1.30 (s, 3H),
.28 – 1.19 (m, 3H), 0.71 (t, J = 7.5 Hz, 3H). 13C{ H} NMR (101 MHz, CDCl two
1
3
,
diasteriomers) δ 178.2, 178.0, 142.1, 141.7, 129.2, 129.2, 128.4, 128.3, 125.9, 125.9, 61.5, 61.3,
61.1, 49.4, 49.2, 37.0, 36.2, 24.5, 24.4, 24.0, 22.6, 14.3, 13.8, 13.6. IR (neat) 3415 (s), 2965 (m),
+
2
361 (s), 1727 (s), 1618 (w), 1456 (w), 1384 (w), 1231 (w). HRMS (ESI) calcd for C H NO
15 24 2
+
[
M+H] 250.1802; found 250.1803.
Ethyl 2-acetamido-4-(4-methoxyphenyl)-2-methylbutanoate (3p) was synthesized from the
1
reaction of 1a with 4b according to the general procedure (31.7 mg, 54% yield). Colorless oil. H
NMR (400 MHz, CDCl ) δ 7.05 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 7.7 Hz, 2H), 6.34 (s, 1H), 4.19
3
(
q, J = 6.9 Hz, 2H), 3.77 (s, 3H), 2.75 – 2.61 (m, 1H), 2.61 – 2.42 (m, 1H), 2.40 – 2.24 (m, 1H),
1
3
1
2
.16 – 2.00 (m, 1H), 1.97 (s, 3H), 1.63 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). C{ H} NMR (101
MHz, CDCl ) δ 174.8, 169.3, 158.0, 133.3, 129.5, 114.0, 62.0, 60.6, 55.5, 37.8, 30.2, 24.2, 23.5,
3
1
4.3. IR (neat) 3292 (w), 2935 (w), 1736 (s), 1658 (s), 1513 (s), 1464 (w), 1246 (s), 1179 (w),
+
+
1122 (w), 1034 (w). HRMS (ESI) calcd for C H NO [M+H] 294.1700; found 294.1696.
1
6
24
4
Ethyl 2-acetamido-4-(4-(tert-butyl)phenyl)-2-methylbutanoate (3q) was synthesized from
the reaction of 1a with 4c according to the general procedure (39.5 mg, 62% yield. White solid.
1
mp. 132-134 °C. H NMR (400 MHz, CDCl ) δ 7.28 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.5 Hz,
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H), 6.33 (s, 1H), 4.44 – 3.87 (m, 2H), 2.80 – 2.64 (m, 1H), 2.63 – 2.48 (m, 1H), 2.45 – 2.28 (m,
1
3
1
H), 2.17 – 2.02 (m, 1H), 1.93 (s, 3H), 1.63 (s, 3H), 1.39 – 1.26 (m, 12H). C{ H} NMR (101
MHz, CDCl ) δ 174.8, 169.3, 149.0, 138.1, 128.3, 125.4, 61.9, 60.6, 37.5, 34.5, 31.5, 30.5, 24.2,
3
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4
4
4
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5
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5
5
5
5
5
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0
1
2
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4
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7
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9
0
1
2
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7
8
9
0
1
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0
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0
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3.5, 14.3. IR (neat) 3296 (w), 2961 (s), 1738 (s), 1656 (s), 1544 (s), 1462 (m), 1375 (m), 1124
+
+
(m), 828 (w). HRMS (ESI) calcd for C H NO [M+H] 320.2220; found 320.2212.
19 30 3
Ethyl 2-acetamido-2-methyl-4-(p-tolyl)butanoate (3r) was synthesized from the reaction of
1
1
a with 4d according to the general procedure (41.3 mg, 74% yield). Colorless oil. H NMR
(400 MHz, CDCl ) δ 7.11 – 6.95 (m, 4H), 6.35 (s, 1H), 4.18 (q, J = 6.9 Hz, 2H), 2.78 – 2.60 (m,
3
1
H), 2.60 – 2.48 (m, 1H), 2.41 – 2.32 (m, 1H), 2.30 (s, 3H), 2.15 – 2.01 (m, 1H), 1.96 (s, 3H),
1
3
1
1.63 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 173.7, 168.3, 137.1,
3
1
2
34.6, 128.2, 127.4, 60.9, 59.6, 36.8, 29.6, 23.2, 22.5, 20.1, 13.3. IR (neat) 3294 (w), 2982 (w),
935 (w), 1738 (s), 1654 (s), 1544 (s), 1446 (w), 1375 (m), 1248 (m), 1191 (m), 1120 (m), 1024
+
+
(m), 810 (s). HRMS (ESI) calcd for C H NO [M+H] 278.1751; found 278.1741.
1
6
24
3
Ethyl 2-acetamido-2-methyl-4-(4-(trifluoromethyl)phenyl)butanoate (3s) was synthesized
from the reaction of 1a with 4e according to the general procedure (38.4 mg, 58% yield).
1
Colorless oil. H NMR (400 MHz, CDCl ) δ 7.51 (d, J = 7.7 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H),
3
6
2
.40 (s, 1H), 4.37 – 3.96 (m, 2H), 2.97 – 2.72 (m, 1H), 2.61 (dd, J = 20.0, 9.8 Hz, 1H), 2.49 –
1
3
1
.31 (m, 1H), 2.26 – 2.06 (m, 1H), 1.97 (s, 3H), 1.63 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). C{ H}
NMR (101 MHz, CDCl ) δ 174.7, 169.4, 145.5, 128.9 (two peaks overlap), 128.4, 125.4 (q, J =
3
7.5 Hz), 62.2, 60.6, 37.0, 31.0, 24.2, 23.7, 14.3. IR (neat) 3296 (w), 2986 (w), 1738 (s), 1656 (s),
1
546 (m), 1377 (w), 1326 (s), 1162 (w), 1122 (s), 1020 (w), 826 (w). HRMS (ESI) calcd for
+
+
C H F NO [M+H] 332.1468; found 332.1463.
1
6
21
3
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Ethyl 2-acetamido-4-(4-fluorophenyl)-2-methylbutanoate (3t) was synthesized from the
1
reaction of 1a with 4f according to the general procedure (31.9 mg, 57% yield). Colorless oil. H
NMR (400 MHz, CDCl ) δ 7.13 – 7.03 (m, 2H), 7.01 – 6.88 (m, 2H), 6.38 (s, 1H), 4.28 – 4.11
3
0
1
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0
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0
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(
m, 2H), 2.81 – 2.63 (m, 1H), 2.63 – 2.44 (m, 1H), 2.40 – 2.24 (m, 1H), 2.16 – 2.01 (m, 1H),
1
3
1
1
1
.99 (s, 3H), 1.62 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.7,
3
69.4, 161.5 (d, J = 243.6 Hz), 136.9 (d, J = 3.2 Hz), 129.9 (d, J = 7.9 Hz), 115.2 (d, J = 21.2
Hz), 62.1, 60.6, 37.6, 30.3, 24.2, 23.6, 14.3. IR (neat) 3294 (w), 2984 (w), 2937 (w), 1736 (s),
+
1
654 (s), 1511 (s), 1375 (w), 1222 (s), 1122 (w), 828 (w). HRMS (ESI) calcd for C H FNO
15 21 3
+
[
M+H] 282.1500; found 282.1492.
Ethyl 2-acetamido-4-(4-chlorophenyl)-2-methylbutanoate (3u) was synthesized from the
reaction of 1a with 4g according to the general procedure (39.7 mg, 67% yield). White solid. mp.
1
7
8-80 °C. H NMR (400 MHz, CDCl ) δ 7.21 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz, 2H), 6.38
3
(s, 1H), 4.30 – 4.11 (m, 2H), 2.83 – 2.63 (m, 1H), 2.63 – 2.42 (m, 1H), 2.42 – 2.21 (m, 1H), 2.17
13
1
–
2.01 (m, 1H), 1.96 (s, 3H), 1.62 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). C{ H} NMR (101 MHz,
CDCl ) δ 174.7, 169.4, 139.7, 131.8, 129.9, 128.6, 62.1, 60.6, 37.3, 30.5, 24.2, 23.6, 14.3. IR
3
(
neat) 3294 (s), 2982 (s), 2939 (s), 1736 (s), 1652 (s), 1544 (s), 1375 (w), 1309 (w), 1246 (w),
+
+
1
2
191 (w), 1093 (w), 1016 (w). HRMS (ESI) calcd for C H ClNO [M+H] 298.1204; found
15 21 3
98.1195.
Ethyl 2-acetamido-4-(4-bromophenyl)-2-methylbutanoate (3v) was synthesized from the
reaction of 1a with 4h according to the general procedure (46.4 mg, 68% yield). White solid. mp.
1
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3-95 °C. H NMR (400 MHz, CDCl ) δ 7.37 (d, J = 7.6 Hz, 2H), 7.01 (d, J = 7.7 Hz, 2H), 6.38
3
(
s, 1H), 4.34 – 4.02 (m, 2H), 2.85 – 2.62 (m, 1H), 2.62 – 2.40 (m, 1H), 2.41 – 2.21 (m, 1H), 2.17
1
3
1
– 2.01 (m, 1H), 1.97 (s, 3H), 1.62 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz,
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The Journal of Organic Chemistry
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CDCl ) δ 174.7, 169.4, 140.3, 131.5, 130.4, 119.9, 62.1, 60.6, 37.2, 30.6, 24.2, 23.6, 14.3. IR
3
(neat) 3296 (w), 2982 (w), 1736 (s), 1654 (s), 1544 (s), 1375 (w), 1248 (w), 1193 (w), 1122 (w),
+
+
1012 (m), 808 (w), 736 (w), 504 (w). HRMS (ESI) calcd for C H BrNO [M+H] 342.0699;
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5
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3
1
1
1
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1
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0
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0
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2
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0
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0
found 342.0694.
Methyl 4-(3-acetamido-4-ethoxy-3-methyl-4-oxobutyl)benzoate (3w) was synthesized from
the reaction of 1a with 4i according to the general procedure (41.1 mg, 64% yield). Colorless oil.
1
H NMR (400 MHz, CDCl ) δ 7.93 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 6.39 (s, 1H),
3
4
2
.28 – 4.09(m, 2H), 3.89 (s, 3H), 2.87 – 2.71 (m, 1H), 2.69-2.53(m, 1H), 2.49 – 2.33(m, 1H),
1
3
1
.20 – 2.06(m, 1H), 1.97 (s, 3H), 1.63 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). C{ H} NMR (101 MHz,
CDCl ) δ 174.7, 169.4, 167.2, 146.8, 129.9, 128.6, 128.2, 62.1, 60.6, 52.2, 37.0, 31.2, 24.2, 23.6,
3
1
1
4.3. IR (neat) 3294 (w), 2984 (w), 1723 (s), 1658 (w), 1542 (w), 1436 (w), 1281 (s), 1181 (w),
+
+
111 (m), 1022 (w). HRMS (ESI) calcd for C H NO [M+H] 322.1649; found 322.1645.
1
7
24
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Ethyl 2-acetamido-4-(3-cyanophenyl)-2-methylbutanoate (3x) was synthesized from the
1
reaction of 1a with 4j according to the general procedure (23.6 mg, 41% yield). Colorless oil. H
NMR (400 MHz, CDCl ) δ 7.51 – 7.45 (m, 1H), 7.42 (s, 1H), 7.41 – 7.32 (m, 2H), 6.41 (s, 1H),
3
4
.32 – 4.09 (m, 2H), 2.90 – 2.71 (m, 1H), 2.67 – 2.48 (m, 1H), 2.47 – 2.18 (m, 1H), 2.20 – 2.04
1
3
1
(
m, 1H), 1.99 (s, 3H), 1.63 (s, 3H), 1.30 (t, J = 7.3 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ
3
1
1
74.6, 169.4, 142.8, 133.2, 132.1, 130.0, 129.3, 119.0, 112.5, 62.2, 60.5, 36.9, 30.8, 24.2, 23.7,
4.3. IR (neat) 3476 (m), 3414 (s), 2361 (s), 1618 (s), 1384 (w), 1120 (w), 617 (w). HRMS (ESI)
+
+
calcd for C H N O [M+H] 289.1547; found 289.1540.
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Ethyl 2-acetamido-2-methyl-4-(4-nitrophenyl)butanoate (3y) was synthesized from the
1
reaction of 1a with 4l according to the general procedure (18.9 mg, 31% yield). Colorless oil. H
NMR (400 MHz, CDCl ) δ 8.12 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.43 (s, 1H), 4.22
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