A Simple Aliphatic Diamine Auxiliary for Palladium-Catalyzed Arylation of Unactivated β-C(sp3)-H Bonds

Article abstract of DOI:10.1002/adsc.201801022

Palladium-catalyzed β-C(sp³)-H arylation of aliphatic acid derivatives was achieved by means of 2-dimethylaminoethylamine auxiliary as a directing group. The β-C(sp³)-H arylation reactions with aryl and heteroaryl iodides efficiently afforded the corresponding arylated hydrocinnamic acid derivatives. Direct β-C(sp³)-H alkynylation, and arene C?H arylation and alkynylation were also realized under the same or slightly modified conditions. The aliphatic diamine auxiliary in the products could be readily removed by methanol in the presence of BF₃ ? OEt₂. In comparison with the widely used bidentate nitrogen-containing directing groups, 2-dimethylaminoethylamine is a simple, cheap, readily available and removable, and atom-economical directing group for C?H functionalization. (Figure presented.).

Full text of DOI:10.1002/adsc.201801022

Title: A Simple Aliphatic Diamine Auxiliary for Palladium-Catalyzed
Arylation of Unactivated β-C(sp³)-H Bonds
Authors: Jiang Lou, Quannan Wang, Yuan He, and Zhengkun Yu
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Simple Aliphatic Diamine Auxiliary for Palladium-Catalyzed
3
Arylation of Unactivated β-C(sp )H Bonds
a, b
a, b
a, b
a, c,
Jiang Lou, Quannan Wang, Yuan He, and Zhengkun Yu *
a
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023,
Peoples Republic of China
b
University of Chinese Academy of Sciences, Beijing 100049, Peoples Republic of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
c
Sciences, 354 Fenglin Road, Shanghai 200032, Peoples Republic of China
Fax: +86-411-8437-9227
E-mail: zkyu@dicp.ac.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
3
Abstract. Palladium-catalyzed β-C(sp )H arylation of aliphatic acid derivatives was achieved by means of 2-
3
dimethylaminoethylamine auxiliary as a directing group. The β-C(sp )H arylation reactions with aryl and heteroaryl
3
iodides efficiently afforded the corresponding arylated hydrocinnamic acid derivatives. Direct β-C(sp )H alkynylation,
and arene CH arylation and alkynylation were also realized under the same or slightly modified conditions. The
aliphatic diamine auxiliary in the products could be readily removed by methanol in the presence of BF
comparison with the widely used bidentate nitrogen-containing directing groups, 2-dimethylaminoethylamine is a
3
2
OEt . In
simple, cheap, readily available and removable, and atom-economical directing group for CH functionalization.
Keywords: diamine; directing groups; palladium; C−H activation; hydrocinnamic acids
Introduction
Transition-metal-catalyzed CH activation has
recently become a promising tool to directly convert
new N,O-bidentate directing group, that is, 3-amino-
-methyl-1H-pyridin-2-one, for the arylation of β- or
1
3
2
[13l]
γ-C(sp )-H, and β- or γ-C(sp )-H bonds.
Although
monodentate auxiliaries can also be used as effective
CH bonds to carbon–carbon and carbon–heteroatom
3
bonds.[1] To control the regioselectivity of CH
directing groups for β-C(sp )H functionalization,
bidentate auxiliaries show much better applicabili-
functionalization, transition-metal catalysis and
directing group chemistry have been used to promote
the challenging direct functionalization of unactivated
[14]
ty.
However, some of these bidentate auxiliaries
are expensive, difficult to be removed, not comer-
cially available, or need to be preassembled by
multistep transformations. Thus, efforts are still in
high demand to explore readily accessible directing
3
[2]
C(sp )−H bond. In this area, many efforts have been
devoted to the exploration of effective directing
groups. In 2005, Yu’s group reported the iodination
3
3
groups for C(sp )H functionalization.
of β-C(sp )H bond by employing an oxazoline ring
[
3]
Based on the structural requirements of an
as the monodentate directing group, and Daugulis et
3
3
effective bidentate directing group for β-C(sp )H
al. documented the arylation of β-C(sp )H bond by
[
4]
functionalization, aliphatic auxiliary 2-dimethyl-
aminoethylamine may be an ideal choice to act as a
simple and readily available N,N-bidentate directing
group. It has been known that N,N’,N’-
trimethylethane-1,2-diamine could be used for intra-
using 8-aminoquinoline auxiliary which has been
widely applied as a bidentate directing group to
effectively assist diverse transition-metal-catalyzed
3
[5]
C(sp )H activation reactions such as arylation,
[6]
[7]
[8]
alkenylation, alkylation, alkynylation, alkoxyla-
2
tion,[
transformations.
9]
[10]
[11]
molecular cyclopalladation via arene C(sp )H or
amination,
carbonylation,
Inspired by the success of this
and other
3
[15a]
[
13]
benzyl C(sp )H activation.
Dialkylamino-imine
auxiliaries enabled ruthenium-catalyzed C-3 alkyla-
tion of furfurals,
bidentate directing group, various N,N-bidentate
[15b]
and a transient N-tosylamino-
directing groups have been developed for the site-
3
imine directing group facilitated palladium-catalyzed
selective C(sp )H functionalization in aliphatic acid
3
[15c]
derivatives[13a-h]
β-C(sp )H arylation. . In 2010, Daugulis’ group
(Scheme 1a), supplemented by a few
3
attempted the arylation of β-C(sp )H bond by using
2-dimethylaminoethylamine auxiliary.
N,X-bidentate directing groups for the same
[5a]
purpose.[5a,13i-k]
However,
Very recently, Maiti, et al. reported a
2-dimethylaminoethylamine as a directing group only
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
exhibited a poor efficiency in comparison to 8-
aminoquinoline, leading to the target product in 45%
target arylated product in 80% isolated yield over a
period of 24 h, and less amount of phenyl iodide (1.5
NMR yield (Scheme 1b), and it was also found to be
equiv) was required by comparison with the
3
[5a]
a
poor [ auxiliary for secondary β-C(sp )H
Pd(OAc)
2
/K
3
PO
4
catalyst system
(Scheme 1c).
16]
arylation. The N,N- and N,X-bidentate auxiliaries
effective for β-C(sp )H functionalization usually
Encouraged by this finding, we further tested the
reaction of the phthaloylalanine derivative (1a) with
3
feature an 8-aminoquinoline, 2-pyridyl, N-heterocy-
cle or a relatively powerful coordinating atom or
group.[
PhI by using the Pd(TFA)
2
/Ag
2
CO catalyst system, a
3
89% yield was achieved for the target arylation
product without racemization. These results reveal
that 2-dimethyl-aminoethylamine auxiliary can act as
13]
3
an effective directing group for β-C(sp )H activation.
3
Herein, we disclose palladium-catalyzed β-C(sp )H
arylation of aliphatic acid derivatives (propionamides)
bearing a simple aliphatic 2-dimethylaminoethyl-
amine auxiliary (Scheme 1c).
Results and Discussion
Initially, the reaction of phthaloylalanine 1a, that is,
N-(2-(dimethyl-aminoethyl)-2-(1,3-dioxoisoindolin-2
-
yl)propanamide, and phenyl iodide (2a) was
conducted to optimize the reaction conditions (Table
1
). Under the same conditions as shown in Scheme
[5a]
1
b, no target arylation product 3a was detected by
H NMR analysis owing to the decomposition of
1
substrate 1a (Table 1, entry 1). Using 10 mol%
Pd(OAc) as the catalyst led to 3a in 48% NMR yield
2
in tert-amyl alcohol at 80 C, revealing the important
Table 1. Screening of reaction conditions.[a]
[
b]
Catalyst
mol%]
Pd(OAc) (5)
Base
Temp Yield
Entry
o
[
[equiv]
[ C]
[%]
[
c]
[d]
3
1
2
3
4
5
6
7
8
9
3
K PO (2.5)
90
80
80
80
80
80
70
60
55
60
60
60
60
60
N.D.
48
48
56
60
85
92
95
91
91
96
2
4
Scheme 1. Directing group strategies for β-C(sp )H
functionalization.
Pd(OAc)
2
(10)
AgOAc (2)
AgOAc (2)
AgOAc (2)
PdCl (10)
2
Pd(TFA)
2
2
(10)
(10)
We reasoned that the ineffectiveness of 2-
dimethylaminoethylamine as an auxiliary for β-
C(sp )H arylation of N,N-dimethyl-N-propionyl-
ethylenediamine (DPEDA) might be attributed to the
weak coordination of its diamino functionality to
palladium(II) acetate during the arylation reaction,
which could not efficiently result in a five-membered
Pd(TFA)
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
O (2)
3
Pd(TFA) (10)
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
(2)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(OAc)
2
2
2
2
2
2
2
2
(10)
(10)
(10)
(10)
(10)
(10)
(5)
(2)
(2)
(2)
[
e]
3
10
(2)
cyclopalladate intermediate to initiate β-C(sp )H
[5a]
[e,f]
1
1
(2)
activation of the amide substrate.
We then
[
e.f]
[g]
envisioned that the reaction efficiency might be
improved through enhancement of the interaction
between the diamine auxiliary of the propionamide
substrate and the catalyst by making the palladium(II)
center more electron-deficient with trifluoroacetate
TFA) anion to replace acetate anion in Pd(OAc)
Thus, we tested the same reaction of DPEDA with
phenyl iodide in the presence of 10 mol% Pd(TFA)
catalyst and 0.8 equiv of Ag CO base in tert-amyl
12
(0.8)
(0.8)
(0.8)
95 (89)
63
[e,f]
1
1
3
4
(10)
23
[
a]
b]
Conditions: 1a (0.1 mmol), 2a (0.15 mmol), tAmOH (1 mL), air, 24 h.
[
1
Determined by H NMR analysis using 1,3,5-trimethoxylbenzene as
(
2
.
the internal standard.
[c]
[d]
[e]
[f]
[5a]
Under the same conditions as shown in Scheme 1b.
2
Not detected.
2
3
1
a (0.3 mmol), 2a (0.45 mmol).
alcohol at 100 C under an air atmosphere. To our
delight, the reaction efficiently occurred to afford the
tAmOH (1.5 mL).
[g]
Isolated yield given in parentheses.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
role of a silver salt (Table 1, entry 2). Pd(TFA)
exhibited an enhanced catalytic activity to promote
the reaction (Table 1, entries 2-4). Among the
2
DPEDA (1b) reacted with 4-biphenyl iodide (2p)
toyield the target -arylated product 4a in 82% yield.
N-(2-(Dimethylaminoethyl)isobutyramide (1c) also
screened silver(I) compounds AgOAc, Ag
2
O, and
Table 2. Scope of aryl iodides (2).[a]
Ag CO , the last one remarkably improved the yield
2
3
to 85% (Table 1, entries 4-6). Because the quick
decomposition of substrate 1a at higher temperature,
o
lowering temperature to 60 C further enhanced the
yield of 3a to 95% (Table 1, entries 6-9). Performing
the reaction on a 0.3 mmol scale of 1a led to 3a in
9
1% yield, and the suitable concentration was found
to be 0.2 M for 1a to yield product 3a in 96% yield
Table 1, entries 10 and 11). In the presence of 0.8
equiv Ag CO the reaction still efficiently proceeded,
(
2
3
affording 3a in 89% isolated yield (Table 1, entry 12).
However, decreasing the catalyst loading to 5 mol%
obviously diminished the reaction efficiency (Table 1,
entry 13). In order to further verify the hypothesis of
the weak coordination between Pd(OAc)
diamino functionality, the reaction was carried out
under the optimized condtions by using Pd(OAc) as
2
and the
2
the catalyst. However, the target product 3a was only
generated in 23% yield, which indicates that the
electrophilicity of Pd(TFA) is crucial for the high
2
catalyst turnover (Table 1, entry 14). It is noteworthy
that the reaction hardly occurred in acetonitrile or
acetic acid solvent.
Under the optimized conditions as shown in entry
2 of Table 1, phthaloylalanine 1a was reacted with
1
an array of aryl and heteroaryl iodides, efficiently
affording potentially important unnatural aminoacid
derivatives that could be applied in the preparation of
bioactive peptides.[ An obvious steric effect was
aroused from o-methoxy and o-fluoro substituents
that the reactions of 1a with o-OMe and o-F-
substituted aryl iodides only formed the target pro-
ducts 3b and 3c in 51-60% yields, whereas the
reaction of 1a with phenyl iodide (2a) formed 3a in a
much higher yield (89%). meta-Methyl and -fluoro-
substituted aryl iodides also reacted well with 1a to
yield products 3d (83%) and 3e (81%), respectively.
17]
4
-Substituents such as p-Me, OMe, F, Cl, Br, CF
3
,
NO , CN, COOEt, and COMe were tolerated to give
2
products 3f-o in good to excellent yields (79-88%),
and no obvious electronic effect was accompanied. It
should be noted that 4-bromo functionalized
compound 3j could be further applied in peptide
[18]
synthesis under Davis conditions. 4-Biphenyl, 3,5-
and 2,4-dimethylphe-nyl iodides exhibited no steric
effect, and their reactions with 1a produced 3p-r in
[a]
Conditions: 1a (0.3 mmol), 2 (0.45 mmol), Pd(TFA)
2
(0.03 mmol),
o
8
4
2-85% yields. Heteroaryl iodides such as 5-indolyl,
-pyrazolyl, 2-pyridyl, and 2-thienyl iodides also
Ag CO (0.24 mmol), tAmOH (1.5 mL), 60 C, air, 24 h. Yields refer to
2
3
the isolated products.
efficiently reacted with 1a to generate the corres-
ponding target products 3s-v (70-92%). The
molecular structures of compounds 3 were further
confirmed by the X-ray single crystal structural
determination of compound 3u (Figure 1).
Next, the scope of the aliphatic acids was explored
under the slightly modified conditions, that is, at
elevated temperature 100 C (Table 3). Propionamide
reacted well to form the corresponding monoarylated
product 4b (60%), accompanied by the formation of
the diarylated product 4b (20%) due to existence of
3
two equivalent reactive β-C(sp )H sites. The simple
carboxylic acid derivatives, that is, α-ethyl, propyl,
and pentyl-functionalized propionamides 1d-f did not
show obvious steric impact on the reaction efficiency,
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
[
e]
and their reactions with 2p gave 4c-e in 74-78%
yields. However, increasing bulkiness at the α-
position of the carbonyl functionality in substrates 1
by introduction of a benzyl or phenyl group, the pro-
2 3
2p (0.9 mmol), Ag CO (0.6 mmol).
duct yields were dramatically diminished from 60%
for 4f to 40% for 4g. It is noteworthy that 4-(iso-
propypl)phenyl-functionalized
propionamide
1i
derived from drug ibuprofen could be arylated to
produce the target product 4h (52%), depicting the
potential application of the protocol in drug diversi-
fication. Both α,α-dimethyl and -diphenyl substituted
propionamides 1j and 1k reacted with 2p to form
products 4i and 4j in moderate yields (50-55%),
exhibiting obvious steric impact on the reaction
efficiency. Methylenes in unstrained cyclohexyl, and
strained cyclopropyl and cyclobutyl rings were
compatible with this transformation. A good yield
(
70%) was obtained for compound 4k, and moderate
Figure 1. Molecular structure of compound 3u.
yields for 4l (54%) and 4m (62%) were reached with
concurrent formation of the diarylated products 4l
(20%) and 4m (26%). Using excess of the aryl iodide
Table 3. Scope of aliphatic acid derivatives (1).[a]
(
3 equiv) led to the diarylation product 4m in 60%
yield.
3
The potential utility of the β-C(sp )H arylation
protocol was further demonstrated by the arylation of
complex amide 1o derived from glycyrrhetinic acid
which could inhibit migration and invasion of human
[19]
gastric cancer cells.
The corresponding arylated
amide product 4n was accessed in 40% yield. The
amide of abietic acid which has been reported to have
[20]
anti-inflammatory and immunomodulatory effects,
reacted with 2p to yield the target product 4o (50%).
In a similar manner, the amide substrate 1q derived
from dehydroabietic acid, a natural product identified
as an efficient BK channel opener which are
potentially useful for the treatment of acute stroke,
[21]
epilepsy, and asthma, reacted to give the arylated
product 4p in 50% yield. It should be noted that
diversification of such complex structures is usually
difficult due to the general low reactivity of these
molecules aside from the carboxylic acid functiona-
lity, which is essential for the biological activity of
them. The unsubstituted aryl iodide, that is, phenyl
iodide (2a), also efficiently reacted with propiona-
mide 1b to give product 4q (80%).
The reaction of an acyclic secondary (methylene)
compound such as 3a with 2p was tried, but the target
arylation product 4r was not obtained. The terminal
β-methyl CH seems to be more reactive than the β-
methelene CH, and the latter can exhibit a steric
effect greater than the former. Thus, the arylation
reaction preferentially occurred at the terminal β-
methyl group. However, some inseperable com-
pounds were also observed with the formation of the
target products. Because these side products were not
successfully isolated and characterized, we could not
exclude the possibility of minor arylation at the β-
methelene group during the reaction. This result has
revealed that acyclic -substituted methylene com-
pounds are not suitable for the arylation in the present
reaction system.
[
a]
Conditions: 1a (0.3 mmol), 2p (0.45 mmol), Pd(TFA)
2
(0.03 mmol),
o
Ag
2
CO
3
(0.24 mmol), tAmOH (1.5 mL), 100 C, air, 24 h. Yields refer
to the isolated products.
[
[
[
b]
c]
d]
o
1
20 C.
4
8 h.
1
Diastereomeric ratios were determined by H NMR analysis.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
3
,3-Dimethylbutyric acid derivative 1s, which
Scheme 3. Gram-scale arylation and removal of the
directing group.
3
possesses three γ-C(sp )H, failed to yield the target
product 4s, presumably due to the difficulty to form
the six-membered cyclopalladate intermediate to
Considering the potential importance of the
resultant unnatural aminoacid derivatives, the gram-
scale reactions of 1a (5 mmol) with phenyl iodide (2a)
and 4-methoxyphenyl iodide (2g) were performed
under the standard conditions, yielding the target
products 3a and 3g in 84-85% yields [Eq. (4)]. A
residual directing group in the arylation products
usually limits the practicality of the synthetic
transformation. To our delight, the aliphatic diamine
3
initiate the γ-C(sp )H activation of the amide
substrate. No target product 4t was obtained either
when pivalic acid was directly used as the substrate.
Then, the reaction scope was extended to CH
2
alkynylation and arene C(sp )H arylation. Phthaloyl-
alanine 1a was reacted with bromoalkyne 5 under the
standard conditions, undergoing β-C(sp )H alkyny-
lation to form the target alkynylation product 6 in
0% yield [Eq. (1)]. ortho-C(sp )H alkynylation of
benzamide 7a was efficiently realized to give product
3
2
6
auxiliary, that is, Me
compounds 3 and 4 could be easily removed through
amide methanolysis in the presence of BF [Eq.s
5) and (6)]. It is noteworthy that the ee values from
2 2 2
NCH CH NH moiety, in
3
OEt
2
(
1
a to 3a (Table 2), and from 3a to 10a [Eq. (5)] were
almost the same, suggesting that no racemization
occurred during the reactions. Thus, propionamides
3
a, 3g, and 4a were efficiently converted to the
corresponding methyl esters 10a-c (72-80%), among
which the N-protected unnatural aminoacid deriva-
tives 10a and 10b are potentially useful building
[22]
blocks for biochemicals.
To probe into the reaction mechanism, control
experiments were performed. 2-Methoxyethylamine
was used to replace the 2-dimethylaminoethylamine
auxiliary in propionamide 11. Under the standard
reaction conditions, compound 11 could not react
with phenyl iodide (2a), suggesting that such a N,O-
bidentate auxiliary was not the compatible directing
3
Scheme 2. Alkynylation and arylation of β-C(sp )H and
C(sp )H.
2
3
group for β-C(sp )H arylation [Eq. (7)]. The
reaction of phthaloylalanine 1a and Pd(TFA)
molar ratio was conducted in tAmOH or CH
2
in a 1:1
CN at
8
(74%) under the standard condition. Elevating the
reaction temperature and prolonging the reaction time
improved the yield to 92% [Eq. (2)]. These results
have revealed that C(sp )H is more facile than
C(sp )H. Both benzamides 7a and 7b underwent o-
3
ambient or elevated temperature to synthesize the
possible reactive intermediate complex [Pd]1a such
as A or B (Scheme 4). Unfortunately, they could not
be successfully isolated due to their instability.
However, the cyclopalladation intermediate species B
was detected in the reaction mixture of 1a and
2
3
2
C(sp )H aryla- tion with 4-biphenyl iodide (2p) to
afford the corresponding arylation products 9a (67%)
and 9b (65%), respectively [Eq. (3)]. These results
reveal that 2-dimethylaminoethylamine can be used
as an effective auxiliary for various CH
functionalization.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
1H and 13C{ H} NMR spectra were recorded on a 400
1
MHz spectrometer and all chemical shift values refer to
1
13
3
CDCl (δ( H), 7.26 ppm and δ( C), 77.16 ppm). X-Ray
crystallographic analysis was achieved by the Analysis
Center, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences. The HRMS analysis was obtained
by ESI on a GC-TOF mass spectrometer. Enantiomeric
excess was determined by chiral HPLC analysis. Optical
rotations were measured by a polarimeter. Column
chromatographic purifications were performed on silica gel.
All the chemical reagents were purchased from
commercial sources and used as received unless otherwise
indicated.
General procedure for the synthesis of hydrocinnamic
acid derivatives (3)
Under an air atmosphere, a mixture of phthaloylalanine (1a)
(
87 mg, 0.3 mmol), aryl iodides (2) (0.45 mmol),
Pd(TFA) (10 mg, 0.03 mmol), and Ag CO (66 mg, 0.24
2
2
3
o
mmol) in 1.5 mL tAmOH was stirred at 60 C for 24 hours.
After cooled to ambient temperature, the reaction mixture
was filtered through a short pad of celite. The filtrate was
concentrated in vacuo, and the resulting residue was
subjected to purification by column chromatography on
Scheme 4. Proposed mechanism.
Pd(TFA)
2
in CH CN by GC-TOF HRMS analysis,
3
indicating formation of a CH activation intermediate
during the reaction (see the Supporting Information
for details).
2 2
silica gel (eluent: CH Cl /MeOH = 70:1, v/v) to afford the
target product 3.
X-Ray crystallographic studies
A plausible mechanism is proposed in Scheme 4.
Initially, phthaloylalanine 1a possessing a relatively
acidic NH functionality interacts with the catalyst
precursor to form N,N-chelated species A through
coordination with the palladium center by the
diamine auxiliary, which then directs CH activation
at the β-position of the propionamide substrate to
generate cyclopalladate species B probably via a
concerted metalation-deprotonation process. Oxida-
tive addition of phenyl iodide (2a) to the Pd(II) center
forms Pd(IV) species C. Subsequent reductive
elimination followed by protonation affords the target
product 3a, regenerating the Pd(II) catalyst and
accomplishing a catalytic cycle.
The Xray diffraction analysis for compound 3u was
carried out on a SMART APEX diffractometer with
graphite-monochromated Mo radiation (λ = 0.71073 Å).
Cell parameters were obtained by global refinement of the
positions of all collected reflections. Intensities were
corrected for Lorentz and polarization effects and
empirical absorption. The structures were solved by direct
2
methods and refined by full-matrix least squares on F . All
non-hydrogen atoms were refined anisotropically. All
hydrogen atoms were placed in calculated positions.
Structure solution and refinement were performed by using
the SHELXL-97 package. The X-ray crystallographic files,
in CIF format, are available from the Cambridge
Crystallographic Data Centre on quoting the deposition
numbers CCDC 1813521 for compound 3u. Copies of this
information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge CB2 IEZ,
UK (Fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.
uk or www: http://www. ccdc.cam.ac.uk).
Conclusion
In summary, we have developed a Pd(II)-catalyzed
direct arylation of unactivated β-C(sp )H bonds with
3
2
-dimethylaminoethylamine auxiliary as an effective
directing group to synthesize diverse hydrocinnamic
acid derivatives. This process exhibits high efficiency,
broad substrate scopes, and high compatibility with
various important functional groups. The present
directing group is simple, cheap, readily available and
removable, and atom-economical, which may be
applied as a promising alternative to the directing
group library for CH functionalization.
(S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
2
-yl)-3-phenylpropanamide (3a): 98 mg, 89% yield,
o
20
white solid, 169-170 C, 99% ee, [α]
D
= -13.25 (c 0.40,
) δ 7.77, 7.67 and 7.14
m each, 2:2:5 H, aromatic CH), 6.58 (br s, 1H, NH), 5.10
1
3 3
CHCl ). H NMR (400 MHz, CDCl
(
(
dd, J = 10.4 and 6.3 Hz, 1H, CH), 3.55 (m, 2H, NHCH
2
),
),
) δ
3
2
1
1
.33 (m, 2H, CHCH
.14 (s, 6H, N(CH
2
), 2.37 (t, J = 6.0 Hz, 2H, CH
2
NMe
2
13
1
3
)
2
). C{ H}NMR (100 MHz, CDCl
3
68.3 and 168.0 (Cq, each, C=O), 137.0 and 131.6 (Cq),
34.2, 129.0, 128.7, 127.0 and 123.5 (aromatic CH), 57.6
(
3
3
CH), 55.6 (CH
2
NMe
). HRMS Calcd for C21
66.1818; Found: 366.1823. HPLC (OD-H column,
2 3 2 2
), 45.1 (N(CH ) ), 37.2 (NHCH ),
Experimental Section
+
4.9 (CHCH
2
23 3 3
H N O [M+H] :
General Considerations
hexane/iPrOH 90:10, 0.8 mL/min, 210 nm) t
= 40.9 min (major).
1
= 34.8 min,
t
2
6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201801022
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
(CH
(CHCH
384.1723; Found: 384.1725.
2
NMe
2 3 2 2
), 45.0 (N(CH ) ), 37.2 (NHCH ), 34.5
+
-yl)-3-(2-methoxyphenyl)propanamide (3b): 61 mg,
2
). HRMS Calcd for C H N O F [M+H] :
21 22 3 3
o
1
5
1% yield, white solid, m.p.: 105-106 C. H NMR (400
) δ 7.74 and 7.65 (m each, 2:2 H, aromatic CH)
.10 (m, 1 H, aromatic CH), 7.00 (dd, J = 7.4 and 1.4 Hz, 1
H, aromatic CH), 6.74 (m, 2 H, NH and aromatic CH),
.68 (t, J =7.4 Hz, 1 H, aromatic CH ), 5.22 (dd, J = 10.5
and 5.1 Hz, 1 H, CH), 3.73 (s, 3 H, OCH ), 3.58 (m, 1 H,
CHCH ), 3.43 (m, 1 H, CHCH ), 3.35 (m, 2 H, NHCH )),
.40 (t, J = 6.0 Hz, 2 H, CH NMe ), 2.17 (s, 6 H, N(CH ).
C{ H}NMR (100 MHz, CDCl ) δ 168.9 and 168.0 (Cq
each, C=O), 157.6, 131.8 and 125.4 (Cq), 134.0, 131.0,
MHz, CDCl
7
3
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(p-tolyl)propenamide (3f): 100 mg, 88% yield,
o
1
white solid, m.p.: 161-162 C. H NMR (400 MHz, CDCl
δ 7.75 and 7.65 (m each, 2:2 H, aromatic CH), 7.04 (d, J =
.9 Hz, 2H, aromatic CH), 6.96 (d, J = 7.9 Hz, 2H,
aromatic CH), 6.65 (br s, 1H, NH), 5.06 (dd, J = 10.2, 6.4
Hz, 1H, CH), 3.51 (m, 2H, NHCH ), 3.30 (m, 2H, CHCH ),
), 2.19 (s, 3H, C CH ),
). C{ H}NMR (100 MHz, CDCl ) δ
3
)
6
3
7
2
2
2
2
2
2
3 2
)
13
1
2
2
3
2
2
1
1
.34 (t, J = 6.0 Hz, 2H, CH
2
1
NMe
2
6
H
4
3
13
.12 (s, 6H, N(CH
3
)
2
3
1
5
(
[
28.4, 123.3, 120.5 and 110.3 (aromatic CH), 57.9 (CH),
5.2 (CH NMe ), 53.6 (OCH ), 45.1 (N(CH ), 37.2
), 30.6 (CHCH ). HRMS Calcd for C22
M+H] : 396.1923; Found: 396.1922.
68.4 and 168.0 (Cq each, C=O), 136.4 and 133.8 (Cq),
34.1, 131.6, 129.3, 128.7 and 123.4 (aromatic CH), 57.5
2
2
3
3 2
)
NHCH
2
+
2
H
25
N
3
O
4
(
3
C
CH), 55.6 (CH
2
NMe
2
), 45.1 (N(CH
CH ). HRMS Calcd for
[M+H] : 380.1974; Found: 380.1970.
3 2 2
) ), 37.2 (NHCH ),
4.42 (CHCH
2
), 21.0 (C
6
H
4
3
+
(
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
22
H
25
N
3
O
3
2
-yl)-3-(2-fluorophenyl)propanamide (3c): 70 mg, 60%
(
2
8
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
o
1
yield, white solid, m.p.: 116-117 C. H NMR (400 MHz,
CDCl ) δ 7.77, 7.68, 7.12 and 6.92 (m each, 2:2:2:2 H,
aromatic CH), 6.83 (br s, 1 H, NH), 5.12 (dd, J = 10.8 and
.3 Hz, 1 H, CH), 3.58 (m, 2 H, NHCH ), 3.36 (m, 2 H,
NMe ), 2.19 (s, 6 H,
). C{ H}NMR (100 MHz, CDCl ) δ 168.2 and
-yl)-3-(4-methoxyphenyl)propanamide (3g): 101 mg,
3
o
1
5% yield, white solid, m.p.: 152-152 C. H NMR (400
) δ 7.73 and 7.63 (m each, 2:2 H, aromatic
MHz, CDCl
3
5
2
CH), 7.05 (d, J = 8.6 Hz, 2H, aromatic CH), 6.68 (m, 3H,
NH and aromatic CH), 5.01 (dd, J = 10.3 and 6.5 Hz, 1H,
C), 3.65 (s, 3H, OMe), 3.46 (m, 2H, NHCH ), 3.29 (m, 2H,
2
CHCH
N(CH
1
1
(
3
3
CHCH
N(CH
2
), 2.44 (t, J = 5.7 Hz, 2 H, CH
2
2
2
13
1
3
)
3
1
67.9 (Cq each, C=O), 161.5 (Cq, d, J = 244.4 Hz, i-C of
F), 134.2 and 123.5 (aromatic CH), 131.7 (Cq), 131.5
d, J = 4.5 Hz, m-C of C F), 128.9 (d, J = 8.1 Hz, o-C of
F), 124.3 (d, J = 3.7 Hz, m-C of C F), 124.1 (p-C of
F), 115.5 (d, J = 21.6 Hz, o-C of C F, aromatic
NMe ), 45.0 (N(CH ), 37.1
). HRMS Calcd for C21
M+H] : 384.1723; Found: 384.1727.
2
), 2.33 (t, J = 6.0 Hz, 2H, CH
2
NMe
2
), 2.11 (s, 6H,
) δ 168.4 and
6 4
C H
(
C
C
13
1
3
)
2
). C{ H}NMR (100 MHz, CDCl
3
6 4
H
68.0 (Cq each, C=O), 158.3, 131.5, and 128.8 (Cq), 134.1,
29.8, 123.4 and 114.0 (aromatic CH), 57.6 (CH), 55.6
6
H
H
4
4
6 4
H
6
6
H
4
CH
2
NMe
3.9 (CHCH
96.1923; Found: 396.1921.
2
), 55.1 (OMe), 45.0 (N(CH
3 2 2
) ), 37.1 (NHCH ),
CH), 57.8 (CH), 54.0 (CH
2
2
3 2
)
+
2
). HRMS Calcd for C22H N O [M+H] :
25 3 4
(
[
NHCH
2
+
), 28.9 (CHCH
2
H
22
N
3
O
3
F
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(4-fluorophenyl)propanamide (3h): 94 mg, 82%
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(m-tolyl)propenamide (3d): 95 mg, 83% yield,
o
1
yield, white solid, m.p.: 163-164 C. H NMR (400 MHz,
CDCl ) δ 7.73 and 7.65 (m each, 2:2 H, aromatic CH),
.09 and 6.81 (m each, 2:2 H, aromatic CH), 6.72 (br s,
H, NH), 5.01 (dd, J = 10.4 and 6.3 Hz, 1H, CH), 3.51 (m,
H, NHCH ), 3.30 (m, 2H, CHCH ), 2.33 (t, J = 6.0 Hz,
H, CH NMe ), 2.09 (s, 6H, N(CH
) δ 168.1 and 167.9 (Cq each, C=O), 161.7
Cq, d, J = 243.5 Hz), 134.2 and 123.4 (aromatic CH),
o
1
white solid, m.p.: 103-104 C. H NMR (400 MHz, CDCl
δ 7.78, 7.67 and 6.94 (m each, 2:2:3 H, aromatic CH), 7.06
t, J = 7.6 Hz, 1 H, aromatic CH), 6.60 (br s, 1 H, NH),
.07 (dd, J = 10.3 and 6.3 Hz, 1 H, CH), 3.50 (m, 2 H,
NHCH ), 3.32 (m, 2 H, CHCH ), 2.36 (t, J = 6.0 Hz, 2 H,
CH NMe ), 2.18 (s, 3 H, Me), 2.13 (s, 6 H, N(CH ).
C{ H}NMR (100 MHz, CDCl ) δ 168.4 and 168.0 (Cq
each, C=O), 138.3, 136.9 and 131.7 (Cq), 134.2, 130.0,
3
)
3
7
1
2
2
(
5
2
2
2
2
13
1
2
2
3 2
) ). C{ H}NMR (100
2
2
3 2
)
MHz, CDCl
3
13
1
3
(
1
32.67 (Cq, d, J = 3.2 Hz), 131.4 (Cq), 130.41 (d, J = 8.0
1
5
(
[
28.6, 127.7, 126.0 and 123.4 (aromatic CH), 57.6 (CH),
5.6 (CH NMe ), 45.1 (N(CH ), 37.2 (NHCH ), 34.8
), 21.3 (Me). HRMS Calcd for C22
Hz, aromatic CH), 115.4 (d, J = 21.2 Hz, ), 57.5 (CH), 55.4
(
(
2
2
3
)
2
2
CH
CHCH
84.1723; Found: 384.1726.
2
NMe
2 3 2 2
), 45.0 (N(CH ) ), 37.1 (NHCH ), 33.9
CHCH
2
+
H
25
N
3
O
3
+
2
). HRMS Calcd for
21 22 3 3
C H N O F [M+H] :
M+H] : 380.1974; Found: 380.1973.
3
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
(
(
S)-3-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)-2-
-yl)-3-(3-fluorophenyl)propenamide (3e): 93 mg, 81%
1,3-dioxoisoindolin-2-yl)propanamide (3i): 97 mg, 81%
o
1
yield, white solid, m.p.: 171-172 C. H NMR (400 MHz,
CDCl ) δ 7.76 and 7.67 (m each, 2:2 H, aromatic CH),
.12 (q, J = 14.0 and 7.7 Hz, 1 H, aromatic CH), 6.93 (d, J
o
1
yield, white solid, m.p.: 159-160 C. H NMR (400 MHz,
CDCl ) δ 7.77, 7.68 and 7.13 (m each, 2:2:4 H, aromatic
CH), 6.69 (br s, 1H, NH), 5.05 (dd, J = 10.3 and 6.4 Hz,
3
3
7
=
7.6 Hz, 1 H, aromatic CH), 6.87 (d, J = 9.6 Hz, 1 H,
1
H, CH), 3.52 (m, 2H, NHCH
.36 (t, J = 5.9 Hz, 2H, CH NMe
C{ H}NMR (100 MHz, CDCl
each, C=O), 135.6, 132.8 and 131.5 (Cq), 134.4, 130.4,
28.9 and 123.6 (aromatic CH), 57.7 (CH), 55.3
CH NMe ), 45.1 (N(CH ), 37.2 (NHCH ),), 34.2
CHCH ). HRMS Calcd for C21 Cl [M+H] :
00.1428; Found: 400.1429.
2
), 3.31 (m, 2H, CHCH
2
),
aromatic CH), 6.79 (m,1 H, aromatic CH), 6.72 (br s, 1 H,
NH), 5.05 (dd, J = 10.5 and 6.1 Hz, 1 H, CH), 3.54 (m, 2 H,
2
2
2
), 2.12 (s, 6H, N(CH
) δ 168.1 and 168.0 (Cq
3
)
2
).
13
1
3
NHCH
CH NMe
MHz, CDCl
J = 244.7 Hz, i-C of C
of C F), 134.3 and 123.5 (aromatic CH), 131.5 (Cq),
30.1 (d, J = 8.3 Hz, m-C of C F), 124.6 (d, J = 2.8 Hz,
p-C of C F), 115.9 (d, J = 21.2 Hz, o-C of C F), 113.9
d, J = 20.8 Hz, o-C of C F), 57.6 (CH), 55.2
2
), 3.31 (m, 2 H, CHCH
), 2.11 (s, 6 H, N(CH
) δ 168.0 and 167.9 (Cq each, C=O), 162.8 (d,
F), 139.6 (Cq, d, J = 7.4 Hz, m-C
2
), 2.35 (t, J = 5.9 Hz, 2 H,
1
3
1
2
2
3 2
) ). C{ H}NMR (100
1
(
(
3
2
2
)
3 2
2
6 4
H
+
2
22 3 3
H N O
6 4
H
4
1
6 4
H
6
H
4
6
H
4
(S)-3-(4-bromophenyl)-N-(2-(dimethylamino)ethyl)-2-
(1,3-dioxoisoindolin-2-yl)propanamide (3j): 112 mg,
(
6
H
4
7
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201801022
o
1
8
4% yield, white solid, m.p.: 158-159 C. H NMR (400
J = 7.0 Hz, 2 H, CO
NHCH
2
CH
2
), 3.58 (d, J = 8.0 Hz, 2 H,
MHz, CDCl
7
2
3
) δ 7.80 and 7.70 (m, 2:2 H, aromatic CH),
2
), 3.29 (m, 2 H, CHCH
2
), 2.34 (t, J = 5.9 Hz, 2 H,
), 1.29 (t, J = 7.1 Hz, 3 H,
). C{ H}NMR (100 MHz, CDCl ) δ 167.9, 167.8
.29 (d, J = 8.4 Hz, 2H, aromatic CH), 7.05 (d, J = 8.4 Hz,
H, aromatic CH), 6.70 (br s, 1H, NH), 5.05 (dd, J = 10.2
), 3.33 (m, 2H,
CH
CH
2
NMe ), 2.09 (s, 6 H, N(CH )
2
3 2
13
1
2
CH
3
3
and 6.5 Hz, 1H, NH), 3.52 (m, 2H, NHCH
2
and 166.4 (Cq each, C=O), 142.4, 131.4 and 129.0 (Cq),
134.3, 129.8, 128.9 and 123.5 (aromatic CH), 60.9
CHCH
N(CH
1
1
2
), 2.36 (t, J = 5.9 Hz, 2H, CH
2
2
NMe
2
), 2.13 (s, 6H,
13
1
3
)
). C{ H}NMR (100 MHz, CDCl
68.0 (Cq each, C=O), 136.1, 131.6 and 120.9 (Cq), 134.4,
31.8, 130.7 and 123.6 (aromatic CH), 57.7 (CH), 55.2
3
) δ 168.1 and
(CO
2
CH
2
), 57.5 (CH), 55.0 (CH
2
NMe
2
), 45.0 (N(CH
CH ). HRMS
[M+H] : 438.2029; Found:
3 2
) ),
37.2 (NHCH
Calcd for
438.2024.
2
), 34.7 (CHCH
C H N O
24 27 3 5
2
), 14.3 (CH
2
3
+
(
(
4
CH
CHCH
44.0923; Found: 444.0925.
2
NMe
2
), 45.1 (N(CH
3
)
2
), 37.2 (NHCH
2
), 34.2
Br [M+H] :
+
2
). HRMS Calcd for C21H N O
22 3 3
(
(
S)-3-(4-acetylphenyl)-N-(2-(dimethylamino)ethyl)-2-
1,3-dioxoisoindolin-2-yl)propanamide (3o): 103 mg,
o
1
(
2
1
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(4-(trifluoromethyl)phenyl)propenamide (3k):
04 mg, 80% yield, white solid, m.p.: 113-114 C. H
) δ 7.77 and 7.69 (m, 2:2 H,
aromatic CH), 7.43 (d, J = 8.0 Hz, 2H, aromatic CH), 7.30
d, J = 8.0 Hz, 2H, aromatic CH), 6.71 (br s, 1H, NH), 5.11
dd, J = 10.4 and 6.2 Hz, 1H, CH), 3.64 (m, 2H, NHCH
), 2.37 (t, J = 5.9 Hz, 2H, CH
). C{ H}NMR (100 MHz, CDCl
68.0 and 167.9 (Cq each, C=O), 141.3 and 131.5 (Cq,
each), 134.4, 129.4 and 123.6 (aromatic CH), 129.3 (q, J =
84% yield, white solid, m.p.: 144-145 C. H NMR (400
MHz, CDCl ) δ 7.71 and 7.65 (m each, 4:2 H, aromatic
3
o
1
CH), 7.23 (d, J = 8.2 Hz, 2 H, aromatic CH), 6.76 (br s, 1
H, NH), 5.08 (dd, J = 9.6 and 7.1 Hz, 1 H, CH), 3.58 (m, 2
NMR (400 MHz, CDCl
3
H, NHCH
2
), 3.34 (m, 2 H, CHCH
NMe
C{ H}NMR (100 MHz, CDCl
2
), 2.45 (s, 3 H, COCH
), 2.09 (s, 6 H, N(CH
) δ 197.7 (Cq, COMe),
3
),
(
(
3
2
1
2.33 (t, J = 6.0 Hz, 2 H, CH
2
2
3
)
2
).
13
1
2
),
),
) δ
3
.34 (m, 2H, CHCH
.13 (s, 6H, N(CH
2
2
NMe
2
167.9 and 167.8 (Cq each, C=O), 142.8 and 135.7 (Cq),
134.3, 131.4, 129.2, 128.7 and 123.5 (aromatic CH), 57.5
1
3
1
3
)
2
3
(CH), 54.9 (CH
34.6 (CHCH ), 26.5 (COCH
23 25 3 4
C H N O [M+H] : 408.1923; Found: 408.1927.
2
NMe
2
), 45.0 (N(CH
3 2 2
) ), 37.2 (NHCH ),
2
3
). HRMS Calcd for
+
1
1
8.4 Hz), 125.6 (q, J = 3.7 Hz, aromatic CH), 124.2 (q, J =
54.4 Hz), , 57.6 (CH), 55.1 (CH NMe ), 45.1 (q, J = 5.5
), 37.2 (NHCH ), 34.6 (CHCH ). HRMS
Calcd for C22 [M+H] : 434.1692; Found:
34.1692.
2
2
(
S)-3-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)-
Hz, N(CH
3
)
2
2
2
ethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide
(3p):
+
22 3 3 3
H N O F
o
1
1
13 mg, 85% yield, white solid, m.p.: 107-108 C. H
4
3
NMR (400 MHz, CDCl ) δ 7.78, 7.68 and 7.49 (m each,
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(4-nitrophenyl)propanamide (3l): 98 mg, 79%
2:2:2 H, aromatic CH), 7.43 (d, J = 8.1 Hz, 2 H, aromatic
CH), 7.38 (t, J = 7.6 Hz, 2 H, aromatic CH), 7.30 (d, J =
7.4 Hz, 1 H, aromatic CH), 7.26 (d, J = 8.2 Hz, 2 H,
aromatic CH), 6.70 (br s, 1 H. NH), 5.15 (dd, J = 10.2 and
o
1
yield, white solid, m.p.: 132-133 C. H NMR (400 MHz,
CDCl ) δ 7.99 and 7.68 (d each, J = 8.6 Hz, 2:2 H,
aromatic CH) 7.74 and 7.33 (m each, 2:2 H, aromatic CH),
.70 (br s, 1 H, NH), 5.09 (dd, J = 10.0 and 6.6 Hz, 1 H,
CH), 3.65 (m, 2 H, NHCH ), 3.29 (m, 2 H, CHCH ), 2.34
t, J = 6.0 Hz, 2 H, CH NMe ), 2.09 (s, 6 H, N(CH ).
C{ H}NMR (100 MHz, CDCl ) δ 167.7 and 167.5 (Cq
each, C=O), 147.0, 145.1 and 131.2 (Cq), 134.5, 129.9,
23.8 and 123.6 (aromatic CH), 57.5 (CH), 54.6
CH NMe ), 45.0 (N(CH ), 37.2 (NHCH ), 34.5
CHCH ). HRMS Calcd for
11.1668; Found: 411.1663.
3
6.5 Hz, 1 H, CH), 3.62 (m, 2 H, NHCH
2
), 3.35 (m, 2 H,
NMe ), 2.15 (s, 6 H,
). C{ H}NMR (100 MHz, CDCl ) δ 168.4 and
6
CHCH
N(CH
2
), 2.39 (t, J = 6.0 Hz, 2 H, CH
2
2
2
13
1
2
2
3
)
3
(
2
2
3
)
2
168.1 (Cq each, C=O), 140.7, 139.7, 136.1 and 131.7 (Cq),
134.3, 129.4, 128.8, 127.4, 127.3, 127.0 and 123.5
1
3
1
3
(aromatic CH), 57.6 (CH), 55.5 (CH
(N(CH ), 37.2 (NHCH ), 34.6 (CHCH ). HRMS Calcd
27 3 3
for C27H N O [M+H] : 442.2131; Found: 442.2131.
2 2
NMe ), 45.1
1
(
(
3
)
2
2
2
+
2
2
3
)
2
2
+
2
C
21
H
22
N
4
O
5
[M+H] :
(
S)-N-(2-(dimethylamino)ethyl)-3-(3,5-dimethylphen-
4
yl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (3q): 97 mg,
o
1
(
(
S)-3-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-2-
82% yield, white solid, m.p.: 120-121 C. H NMR (400
MHz, CDCl ) δ 7.78, 7.68 and 6.78 (m each, 2:2:3 H,
aromatic CH), 6.60 (br s, 1 H, NH), 5.06 (dd, J = 10.1 and
6.4 Hz, 1 H, CH), 3.42 (m, 4 H, NHCH and CHCH ), 2.35
(t, J = 6.0 Hz, 2 H, CH NMe ), 2.15 and 2.14 (s each, 12 H,
). C{ H}NMR (100 MHz, CDCl ) δ
1,3-dioxoisoindolin-2-yl)propanamide (3m): 96 mg,
3
o
1
8
2% yield, white solid, m.p.: 122-123 C. H NMR (400
) δ 7.73 and 7.66 (m, 2:2 H, aromatic CH),
.42 and 7.26 (d, J = 8.1 Hz, 2:2 H, aromatic CH), 6.71 (br
s, 1 H, NH), 5.05 (dd, J = 10.6 and 6.0 Hz, 1 H, CH), 3.55
m, 2H, NHCH ), 3.30 (m, 2 H, CHCH ), 2.33 (t, J = 6.0
Hz, 2 H, CH NMe ), 2.09 (s, 6 H, N(CH
100 MHz, CDCl ) δ 167.7 and 167.5 (Cq each, C=O),
42.9, 131.2 and 110.7 (Cq), 134.4, 132.3, 129.8 and 123.5
MHz, CDCl
7
3
2
2
2
2
13
1
N(CH
3
)
2
and CH
3
3
(
2
2
168.4 and 168.1 (Cq each, C=O), 138.2, 136.8 and 131.
(Cq), 134.2, 128.6, 126.8 and 123.5 (aromatic CH), 57.6
1
3
1
2
2
3 2
) ). C{ H}NMR
(
1
3
(CH), 55.7 (CH
34.8 (CHCH ), 21.2 (Me). HRMS Calcd for C23
[M+H] : 394.2131; Found: 394.2129.
2 2 3 2 2
NMe ), 45.1 (N(CH ) ), 37.2 (NHCH ),
2
27 3 3
H N O
+
(
(
(
aromatic CH), 118.7 (Cq, CN), 57.4 (CH), 54.6
CH NMe ), 45.0 (N(CH ), 37.1 (NHCH ), 34.8
CHCH ). HRMS Calcd for
91.1770; Found: 391.1774.
2
2
3
)
2
2
(
S)-N-(2-(dimethylamino)ethyl)-3-(3,4-dimethylphen-
+
2
C
22
H
22
N
4
O
3
[M+H] :
yl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (3r): 100
3
1
3
mg, 85% yield, yellow liquid. H NMR (400 MHz, CDCl )
(
S)-ethyl 4-(3-((2-(dimethylamino)ethyl)amino)-2-(1,3-
δ 7.70 (m, 5 H, NH and aromatic CH), 6.88 (m, 3 H,
dioxoisoindolin-2-yl)-3-oxopropyl)benzoate (3n): 108
aromatic CH), 5.06 (dd, J = 10.8 and 5.5 Hz, 1 H, CH),
o
1
mg, 82% yield, white solid, m.p.: 154-155 C. H NMR
400 MHz, CDCl ) δ 7.81 and 7.21 (d each, J = 7.5 Hz, 2:2
H, aromatic CH), 7.72 and 7.63 (m, 2: 2 H, aromatic CH),
.71 (br s, 1 H, NH), 5.08 (t, J = 8.3 Hz, 1 H, CH), 4.25 (q,
3.48 (m, 4 H, CHCH
5.9 Hz, 2 H, CH NMe
2.05 (s each, 3:3 H, Me). C{ H}NMR (100 MHz, CDCl
2
and NHCH
2
), 2.83 (dd, J = 11.0 and
(
3
2
2
), 2.51 (s, 6 H, N(CH
3 2
)
), 2.10 and
13
1
3
)
6
δ 169.2 and 168.1 (Cq each, C=O), 136.7, 134.9, 134.3 and
8
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201801022
2 19 21 3 3
). HRMS Calcd for C H N O S
[M+H]+:
1
32.0 (Cq), 134.0, 130.3, 129.8, 126.3 and 123.4 (aromatic
(CHCH
372.1382; Found: 372.1382.
CH), 58.1 (CH), 55.3 (CH NMe ), 44.4 (N(CH ), 36.0
2
2
3 2
)
(
NHCH
Calcd for
94.2129.
2
), 34.3 (CHCH
2
), 19.6 and 19.4 (Me). HRMS
+
C
23
H
27
N
3
O
3
[M+H] : 394.2131; Found:
General procedure for the the synthesis of
hydrocinnamic acid derivatives (4).
3
(
2
9
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
Under an air atmosphere, a mixture of aliphatic acids
derivatives (1) (0.3 mmol), 4-iodobiphenyl (2p) (126 mg,
-yl)-3-(1-tosyl-1H-indol-5-yl)propanamide (3s): 155 mg,
o
1
2% yield, white solid, 177-178 C. H NMR (400 MHz,
) δ 7.76 (d, J = 8.7 Hz, 1 H, aromatic CH), 7.65 and
.14 (m each, 6:3 H, aromatic CH), 7.56 (br s, 1 H, NH),
.42 (d, J = 3.6 Hz, 1 H, aromatic CH), 7.32 (s, 1 H,
0
2 2 3
.45 mmol), Pd(TFA) (10 mg, 0.03 mmol), and Ag CO
CDCl
7
7
3
(
66 mg, 0.24 mmol) in 1.5 mL tAmOH was stirred at 100
o
C for 24 hours. After cooled to ambient temperature, the
reaction mixture was filtered through a short pad of celite.
The filtrate was concentrated in vacuo, and the resulting
residue was subjected to purification by column
aromatic CH), 6.47 (d, J = 3.6 Hz, 1 H, aromatic CH), 5.11
dd, J = 10.6 and 5.7 Hz, 1 H, CH), 3.67 (m, 1 H, CHCH ),
.53 (m, 2 H, NHCH ), 3.40 (m, 1 H, CHCH ), 2.72 (dd, J
11.2 and 6.4 Hz, 2 H, CH NMe ), 2.40 (s, 6 H, N(CH ),
.30 (s, 3 H, Me of Ts). C{ H}NMR (100 MHz, CDCl
δ 168.9 and 168.1 (Cq each, C=O), 145.0, 135.2, 133.8,
(
3
=
2
2
2
2
2 2
chromatography on silica gel (eluent: CH Cl /MeOH =
2
2
3 2
)
1
3
1
7
0:1, v/v) to afford the target product 4.
3
)
3
-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-
1
1
(
32.2 and 131.1 (Cq), 133.8, 131.7, 130.0, 126.8, 126.6,
25.6, 123.4, 121.8, 113.6 and 109.1 (aromatic CH), 58.0
1
propenamide (4a): 73 mg, 82% yield, yellow liquid. H
NMR (400 MHz, CDCl ) δ 7.56 (d, J = 7.3 Hz, 2 H,
aromatic CH), 7.51 (d, J = 8.1 Hz, 2 H, aromatic CH), 7.42
t, J = 7.6 Hz, 2 H, aromatic CH), 7.31 (m, 3 H, aromatic
CH), 6.45 (br s, 1 H, NH), 3.37 (q, J = 5.0 Hz, 2 H,
NHCH ), 3.01 (t, J = 7.6 Hz, 2 H, (C=O)CH CH ), 2.53 (m,
H, (C=O)CH CH and CH NMe ), 2.29 (s, 6 H, N(CH ).
C{ H}NMR (100 MHz, CDCl ) δ 172.5 (Cq, C=O),
141.0, 140.1 and 139.2 (Cq), 129.0, 128.9, 127.6, 127.2
and 127.0 (aromatic CH), 58.0 (CH NMe ), 44.7
N(CH ), 38.2 (NHCH ), 36.1 ((C=O)CH ), 31.4
((C=O)CH CH ). HRMS Calcd for C19 O [M+H] :
297.1967; Found: 297.1967.
3
CH), 55.4 (CH
2
NMe
2 3 2 2
), 45.0 (N(CH ) )), 36.2 (NHCH ),
3
4.7 (CHCH ), 21.6 (Me of Ts). HRMS Calcd for
2
(
+
30 30 4 5
C H N O S [M+H] : 559.2015; Found: 559.2011.
(
2
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(1-tosyl-1H-pyrazol-4-yl)propanamide (3t): 126
2
2
2
4
2
2
2
2
3 2
)
o
1
13
1
mg, 83% yield, white solid, m.p.: 87-88 C. H NMR (400
MHz, CDCl ) δ 7.88 and 7.52 (s each, 1 H, aromatic CH),
.75 (m, 6 H, aromatic CH), 7.20 (d, J = 8.2 Hz, 2 H,
aromatic CH), 6.61 (br s, 1 H, NH), 4.92 (dd, J = 10.4 and
.1 Hz, 1 H, CH), 3.37 (m, 4 H, CHCH and NHCH ), 2.36
m, 5 H, CH NMe and Me of Ts), 2.11 (s, 6 H, N(CH ).
C{ H}NMR (100 MHz, CDCl ) δ 167.8 and 167.6 (Cq
each, C=O), 145.7, 145.6, 134.0 and 129.8 (Cq), 134.5,
31.4, 130.0, 128.0, 123.7 and 120.0 (aromatic CH), 57.5
CH), 54.4 (CH NMe ), 45.0 (N(CH ), 37.1 (NHCH ),
), 21.8 (Me of Ts). HRMS Calcd for
3
3
7
2
2
(
3
)
2
2
2
+
6
2
2
2
2
24 2
H N
(
2
2
3 2
)
1
3
1
3
3
-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-2-
methylpropanamide (4b): 56 mg, 60% yield, yellow
1
(
2
1
liquid. H NMR (400 MHz, CDCl
3
) δ 7.51 (m, 1 H, NH),
2
2
3
)
2
2
7
2
7
.48 (d, J = 7.3 Hz, 2 H, aromatic CH), 7.43 (d, J = 8.1 Hz,
H, aromatic CH), 7.34 (t, J = 7.6 Hz, 2 H, aromatic CH),
.23 (d, J = 8.5 Hz, 3 H, aromatic CH), 3.43 (m, 2 H,
3.7 (CHCH
2
+
25 27 5 5
C H N O S [M+H] : 510.1811; Found: 510.1810.
(
2
(
(
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)propen-amide
NHCH
CH NMe
H, CH(CH
Cq, C=O), 140.7, 139.0 and 138.8 (Cq), 129.7, 128.8,
127.2, 126.9 and 126.8 (aromatic CH), 58.0 (CH NMe ),
43.7 (CH), 43.0 (N(CH ), 39.9 (CH(CH )), 34.8
)). HRMS Calcd for C20
M+H] : 311.2123; Found: 311.2123.
2
), 2.90 (m, 2 H, CH(CH
2
)), 2.67 (m, 3 H, CH and
), 1.14 (d, J = 6.3 Hz, 3
)). 13C{ H}NMR (100 MHz, CDCl
) δ 176.5
2
2
), 2.44 (s, 6 H, N(CH
3
3 2
)
1
o
1
3u): 102 mg, 78% yield, white solid, 78-79 C. H NMR
400 MHz, CDCl ) δ 7.74 and 7.43 (m each, 5:2 H,
3
(
3
aromatic CH), 7.13 (br s, 1 H, NH), 5.28 (dd, J = 8.4 and
.5 Hz, 1 H, CH), 3.79 (m, 2 H, CHCH ), 3.35 (m, 2 H,
NHCH ), 2.40 (t, J = 6.1 Hz, 2 H, CH NMe ), 2.14 (s, 6 H,
N(CH ). C{ H}NMR (100 MHz, CDCl
2
2
6
2
)
3 2
2
(
[
NHCH
2
+
), 17.7 (CH(CH
3
26 2
H N O
2
2
2
13
1
3
)
2
3
) δ 168.3 and
1
4
68.1 (Cq each, C=O), 158.8 and 131.9 (Cq), 147.7 (q, J =
3
-([1,1'-biphenyl]-4-yl)-2-([1,1'-biphenyl]-4-ylmeth-yl)-
9.0 Hz, α-C of CF
3
), 138.2, 134.2, 126.8 and 123.5
N-(2-(dimethylamino)ethyl)propanamide (4b): 28 mg,
(
2
(
aromatic CH), 121.2 (q, J = 272.6 Hz, CF
.6 Hz, β-C of CF ), 57.8 (CH), 53.2 (CH
N(CH ), 37.3 (NHCH ), 36.3 (CHCH ). HRMS Calcd
[M+H] : 435.1644; Found: 435.1643.
3
), 118.6 (q, J =
o
1
2
0% yield, white solid, m.p.: 102-103 C. H NMR (400
MHz, CDCl ) δ 7.53 (m, 9 H, aromatic CH), 7.41 (t, J =
.5 Hz, 4 H, aromatic CH), 7.32 (d, J = 8.1 Hz, 5 H,
aromatic CH), 7.23 (br s, 1 H, NH), 3.29 (q, J = 5.1 Hz, 2
H, NHCH ), 3.04 (m, 2 H, CH(CH )), 2.94 (m, 1 H, CH),
.85 (m, 2 H, CH(CH )), 2.50 (t, J = 5.3 Hz, 2 H,
CH NMe ), 2.25 (s, 6 H, N(CH
MHz, CDCl ) δ 174.7 (Cq, C=O), 140.7, 139.0 and 138.7
Cq), 129.8, 128.8, 127.2, 127.0 and 126.9 (aromatic CH),
8.0 (CH NMe ), 51.1 (CH), 43.7 (N(CH ), 38.5
(NHCH ), 34.81 (CH(CH )). HRMS Calcd for C32
[M+H] : 463.2749; Found: 463.2747.
3
2
NMe ), 45.1
2
3
3
)
2
2
+
2
7
21 4 3 3
for C21H N O F
(
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
2
2
2
2
2
-yl)-3-(thiophen-2-yl)propanamide (3v): 78 mg, 70%
o
1
13
1
yield, white solid, 162-163 C. H NMR (400 MHz, CDCl
δ 7.82, 7.72, and 7.06 (m each, 2:2:1 H, aromatic CH),
6
5
3
)
2
2
3 2
) ). C{ H}NMR (100
3
(
5
.80 (d, J = 3.2 Hz, 2 H, aromatic CH), 6.66 (s, 1 H, NH),
.05 (dd, J = 9.8 and 6.5 Hz, 1 H, CH), 3.80 (m, 2 H,
2
2
3 2
)
NHCH
2
), 3.33 (m, 2 H, CHCH
2
), 2.40 (m, 2 H, CH
2
NMe
2
),
2
+
2
34 2
H N O
1
3
1
2
1
1
5
.14 (s, 6 H, NMe
2
). C{ H}NMR (100 MHz, CDCl
3
) δ
67.9 and 167.8 (Cq, C=O), 139.2 and 131.8 (Cq), 134.3,
27.0, 126.4, 124.7 and 123.6 (aromatic CH). 57.6 (CH),
2
-([1,1'-biphenyl]-4-ylmethyl)-N-(2-(dimethylamino)-
ethyl)butanamide (4c): 72 mg, 74% yield, yellow liquid.
5.8 (CH
2
NMe
2
), 45.1 (NMe
2
), 37.2 (NHCH
2
), 29.1
1
H NMR (400 MHz, CDCl
3
) δ 7.46 (d, J = 7.5 Hz, 2 H,
9
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201801022
o
1
aromatic CH), 7.41 (d, J = 8.1 Hz, 2 H, aromatic CH), 7.33
3
m.p.: 122-123 C. H NMR (400 MHz, CDCl ) δ 7.70 (t, J
(
t, J = 7.6 Hz, 2 H, aromatic CH), 7.23 (m, 3 H, aromatic
CH), 7.16 (t, J = 4.7 Hz, 1 H, NH), 3.40 and 3.25 (m each,
:1 H, NHCH ), 2.84 (m, 1 H, CH ), 2.68 (m, 2 H, CH
and CH), 2.53 – 2.35 (m, 2 H, CH N(CH ), 2.29 (s, 6 H,
N(CH ), 1.64 (m, 1 H, CH CH ), 1.49 (m, 1 H, CH CH ),
.86 (t, J = 7.4 Hz, 3 H, CH ). C{ H}NMR (100
MHz, CDCl ) δ 175.5 (Cq, C=O), 140.7, 139.1 and 138.8
Cq), 129.7, 128.8, 127.2, 126.8 and 126.7 (aromatic CH),
7.9 (CH N(CH ), 51.0 (CH), 43.9 (N(CH ), 38.5
), 35.1 (CH ), 25.7 (CH CH ), 12.0
). HRMS Calcd for
= 4.8 Hz, 1 H, NH), 7.53 (d, J = 7.7 Hz, 2 H, aromatic CH),
7.46 (d, J = 7.9 Hz, 4 H, aromatic CH), 7.40 (t, J = 7.6 Hz,
2 H, aromatic CH), 7.30 (t, J = 6.6 Hz, 5 H, aromatic CH),
7.22 (t, J = 7.3 Hz, 1 H, aromatic CH), 3.88 (dd, J = 9.5
1
2
2
2
2
3 2
)
3
)
2
2
3
2
3
and 6.1 Hz, 1 H, CH), 3.50 (m, 2 H, NHCH
CHCH ), 3.04 (m, 1 H, CHCH ), 2.79 (m, 1 H, CH
2.69 (m, 1 H, CH NMe ), 2.40 (s, 6 H, N(CH
C{ H}NMR (100 MHz, CDCl
2
), 3.31 (m, 1 H,
1
3
1
0
2
CH
3
2
2
2
NMe
2
),
).
3
2
2
3
)
2
13
1
(
5
(
(
3
3
) δ 173.6 (Cq, C=O),
2
3
)
2
3
)
3
2
140.8, 139.6, 139.0 and 138.8 (Cq), 129.8, 128.9, 128.7,
128.1, 127.3, 127.2, 126.9 and 126.8 (aromatic CH), 57.8
CH
CH
2
2
N(CH
CH
3
)
2
2
2
+
3
C
21
H
28
N
2
O
[M+H] :
(CH
35.2 (NHCH
73.2280; Found: 373.2279.
2
NMe
2
), 54.7 (CH), 43.8 (N(CH
3 2 2
) ), 39.1 (CHCH ),
+
25.2280; Found: 325.2280.
2
). HRMS Calcd for C25H N O [M+H] :
28 2
3
2
-([1,1'-biphenyl]-4-ylmethyl)-N-(2-(dimethylamino)-
ethyl)pentanamide (4d): 77 mg, 75% yield, yellow solid.
H NMR (400 MHz, CDCl ) δ 7.50 (m, 2 H, aromatic CH),
3
3-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-2-
(4-isobutylphenyl)propenamide (4h): 67 mg, 52% yield,
white solid, m.p.: 131-132 C. H NMR (400 MHz, CDCl )
3
δ 7.80 (t, J = 5.3 Hz, 1 H, NH), 7.47 (d, J = 7.4 Hz, 2 H,
aromatic CH), 7.40 (d, J = 8.1 Hz, 2 H, aromatic CH), 7.33
(m, 4 H, aromatic CH), 7.23 (d, J = 8.4 Hz, 3 H, aromatic
CH), 7.01 (d, J = 7.9 Hz, 2 H, aromatic CH), 3.83 (dd, J =
1
o
1
7
2
7
.44 (d, J = 8.1 Hz, 2 H, aromatic CH), 7.36 (t, J = 7.5 Hz,
H, aromatic CH), 7.26 (t, J = 7.3 Hz, 1 H, aromatic CH),
.20 (d, J = 8.1 Hz, 2 H, aromatic CH), 6.33 (br s, 1 H,
NH), 3.20 (m, 2 H, NHCH
m, 1 H, CH), 2.34 (m, 2 H, CH
CHCH ), 2.08 (s, 6 H, N(CH ), 1.33 (m, 4 H, CH
t, J = 7.2 Hz, 3 H, CH CH
) δ 175.2 (Cq, C=O), 140.9, 139.3 and 138.9 (Cq),
2
), 2.87 (m, 1 H, CHCH
N(CH ), 2.18 (m, 1 H,
), 0.86
). C{ H}NMR (100 MHz,
2
), 2.71
(
2
3 2
)
2
3
)
3
2
2
9.4 and 6.1 Hz, 1 H, (C=O)CH), 3.45 (m, 2 H, NHCH
3.26 (m, 1 H, (C=O)CHCH ), 2.98 (m, 1 H, (C=O)CHCH
2.72 (m, 2 H, CH N(CH ), 2.35 (m, 8 H, N(CH and
CH ), 1.77 (J = 1 H, CH), 0.83 (d, J = 6.6 Hz, 6 H, CH ).
) δ 173.8 (Cq, C=O),
2
),
1
3
1
(
2
2
2
),
CDCl
3
2
3
)
2
3 2
)
1
(
3
29.5, 128.8, 127.1, 126.9 and 126.8 (aromatic CH), 57.9
CH N(CH ), 49.9 (CH), 44.6 (N(CH ), 39.0 (CH ),
6.0 (CH ), 34.9 (CH CH CH ), 20.8 (CH CH CH ), 14.1
CH CH ). HRMS Calcd for C22 O [M+H] :
39.2436; Found: 339.2436.
2
3
13
1
2
3
)
2
3
)
2
2
2
C{ H}NMR (100 MHz, CDCl
3
2
2
2
3
2
3
140.5, 138.8, 138.7 and 136.7 (Cq), 129.6, 129.2, 128.7,
127.6, 127.1, 126.7 and 126.6 (aromatic CH), 57.2
+
(
CH
2
2
3
30 2
H N
3
(CH
2
N(CH
3
)
2
), 53.9 (CH), 44.9 ((C=O)CHCH
), 39.0 (CH CH(CH ), 35.1 (NHCH
), 22.3 (CH(CH ). HRMS Calcd for
O [M+H] : 429.2906; Found: 429.2906.
2
), 43.4
(
(
N(CH
CH(CH
3
)
2
2
3
)
)
3 2
2
2
), 30.0
2
-([1,1'-biphenyl]-4-ylmethyl)-N-(2-(dimethylamino)-
3
)
2
ethyl)heptanamide (4e): 86 mg, 78% yield, white solid,
+
C
29
H
36
N
2
o
1
m.p.: 130-131 C. H NMR (400 MHz, CDCl
3
) δ 7.50 (m,
H, aromatic CH), 7.44 (d, J = 8.1 Hz, 2 H, aromatic CH),
.35 (t, J = 7.6 Hz, 3 H, aromatic CH), 7.26 (t, J = 3.5 Hz,
H, aromatic CH), 3.48 (m, 1 H, NHCH ), 3.27 (m, 1 H,
), 2.86 (m, 1 H, CH), 2.76 (m, 2 H, CHCH ), 2.51
m, 2 H, CH N(CH ), 2.34 (s, 6 H, N(CH ), 1.65 (m, 1
H, CHCH CH ), 1.48 (m, 1 H, CHCH CH ), 1.24 (m, 6 H,
CH ), 0.81 (t, J = 5.5 Hz, 3 H, CH CH
100 MHz, CDCl ) δ 175.6 (Cq, C=O), 140.6, 139.1 and
38.7 (Cq), 129.7, 128.8, 127.2, 126.8 and 126.7 (aromatic
N(CH ), 49.2 (CH), 43.7 (N(CH ), 38.7
), 34.8 (NHCH ), 32.7, 31.8, 27.3 and 22.5 (CH ),
4.1 (CH CH ). HRMS Calcd for C24
67.2749; Found: 367.2751.
2
7
3
3-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-2,2-
dimethylpropanamide (4i): 54 mg, 55% yield, white solid,
o
1
2
3
m.p.: 85-86 C. H NMR (400 MHz, CDCl ) δ 7.55 (d, J =
NHCH
2
2
7.4 Hz, 2 H, aromatic CH), 7.47 (d, J = 8.1 Hz, 2 H,
aromatic CH), 7.41 (t, J = 7.6 Hz, 3 H, aromatic CH), 7.32
(t, J = 7.3 Hz, 1 H, aromatic CH), 7.23 (d, J = 8.1 Hz, 2 H,
(
2
3
)
2
3 2
)
2
2
2
2
1
3
1
2
2
3
). C{ H}NMR
aromatic CH), 3.59 (q, J = 5.5 Hz, 2 H, NHCH
2 H, CH N(CH ), 2.89 (s, 2 H, CCH ), 2.60 (s, 6 H,
N(CH ), 1.28 (s, 6 H, C(CH ). C{ H}NMR (100 MHz,
CDCl ) δ 178.3 (Cq, C=O), 140.9, 139.2 and 137.5 (Cq),
131.0, 128.9, 127.3, 127.0 and 126.6 (aromatic CH), 58.8
(CH N(CH ), 46.4 (CCH ), 44.1 (N(CH ), 43.8 (CCH ),
35.1 (CH N(CH ), 25.3 (C(CH ). HRMS Calcd for
O [M+H] : 325.2280; Found: 325.2278.
2
), 2.94 (m,
(
3
2
3
)
2
2
13
1
1
3
)
2
3 2
)
CH), 58.0 (CH
CHCH
2
3
)
2
3
)
2
3
(
2
2
2
+
1
3
2
3
H
34
N
2
O [M+H] :
2
3
)
2
2
3
)
2
2
2
3
)
2
+
3 2
)
21 28 2
C H N
3
-([1,1'-biphenyl]-4-yl)-2-benzyl-N-(2-(dimethyl-
amino)ethyl)propenamide (4f): 70 mg, 60% yield, white
3-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-2,2-
o
1
solid, m.p.: 55-56 C. H NMR (400 MHz, CDCl
m, 3 H, NH and aromatic CH), 7.42 (d, J = 8.1 Hz, 2 H,
aromatic CH), 7.33 (t, J = 7.6 Hz, 2 H, aromatic CH), 7.23
m, 3 H, aromatic CH), 7.17 (d, J = 4.6 Hz, 4 H, aromatic
CH), 7.08 (m, 1 H, aromatic CH), 3.25 (q, J = 3.1 Hz, 2 H,
NHCH ), 2.91 (m, 3 H, CH and CH ), 2.75 (m, 2 H, CH ),
.56 (t, J = 5.5 Hz, 2 H, CH N(CH ), 2.30 (s, 6 H,
). C{ H}NMR (100 MHz, CDCl ) δ 174.9 (Cq,
3
) δ 7.50
diphenylpropanamide (4j): 68 mg, 50% yield, white solid,
o
1
(
3
m.p.: 114-115 C. H NMR (400 MHz, CDCl ) δ 7.46 (d, J
= 7.6 Hz, 2 H, aromatic CH), 7.34 (t, J = 7.6 Hz, 3 H,
aromatic CH), 7.20 (m, 13 H, aromatic CH and NH), 6.73
(
(d, J = 8.1 Hz, 2 H, aromatic CH), 3.77 (s, 2 H, CCH
3.59 (m, 2 H, NHCH ), 2.79 (t, J = 5.5 Hz, 2 H,
CH N(CH ), 2.38 (s, 6 H, N(CH
MHz, CDCl ) δ 174.5 (Cq, C=O), 142.3, 140.9, 138.8 and
136.8 (Cq), 131.5, 129.6, 128.7, 128.0, 127.1, 126. and
126.0 (aromatic CH), 62.9 (CH N(CH ), 57.4 (Cq), 43.8
(N(CH ), 43.7 (CH ), 35.8 (NHCH ). HRMS Calcd for
31 32 2
C H N O [M+H] : 449.2593; Found: 449.2594.
2
),
2
2
2
2
13
1
2
2
3
)
2
2
3
)
2
3 2
) ). C{ H}NMR (100
13
1
N(CH
3
)
2
3
3
C=O), 140.6, 139.5, 138.9 and 138.6 (Cq), 129.8, 129.3,
1
5
28.8, 128., 127.2, 126.9, 126.8 and 126.2 (aromamtic CH),
7.8 (CH N(CH ), 50.8 (CH), 43.3 (N(CH ), 38.8
), 38.3 (CH ), 34.4 (CH ). HRMS Calcd for
O [M+H] : 387.2436; Found: 387.2436.
2
3 2
)
2
3
)
2
3
)
2
3
)
2
2
2
+
(
NHCH
2
2
2
+
C
26 30 2
H N
2
-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-
3
-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-2-
cyclohexanecarboxamide (4k): 74 mg, 70% yield, white
solid, m.p.: 99-100 C. The coupling constants of the
o
phenylpropanamide (4g): 45 mg, 40% yield, white solid,
1
0
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
proton NMR spectrum suggest that 4k is the cis-
δ 7.80 (t, J = 5.0 Hz, 1 H, NH), 7.52 (m, 8 H, aromatic CH),
7.39 (t, J = 7.9 Hz, 8 H, aromatic CH), 7.30 (t, J = 7.3 Hz,
1
diastereomer. H NMR (400 MHz, CDCl
3
) δ 7.46 and 7.33
(
m each, 4:4 H, aromatic CH), 7.23 (d, J = 5.1 Hz, 1 H,
2
2 H, aromatic CH), 3.91 (m, 3 H, NHCH and cyclobutyl
aromatic CH), 7.09 (br s, 1 H, NH), 3.32 (m, 1 H), 3.12 (m,
CH), 3.45 (m, 1 H, cyclobutyl CH), 3.15 (m, 2 H,
1
2
H), 2.89 (m, 1 H), 2.78 (m, 1 H), 2.66 (m, 1 H), 2.40 (m,
H), 2.25 (s, 6 H), 1.90 (m, 3 H), 1.68 (m, 2 H), 1.48 (m, 1
cyclobutyl CH), 2.63 (m, 1 H, cyclobutyl CH), 2.41 (t, J =
5.4 Hz, 2 H, CH
2
NMe
C{ H}NMR (100 MHz, CDCl
140.7, 140.3 and 138.5 (Cq), 128.8, 127.8, 127.2, 126.8
and 126.5 (aromatic CH), 57.6 (CH NMe ), 52.8
((C=O)CHCH), 43.1 (N(CH ), 38.3 (NHCH ), 34.3 and
2
), 2.29 (s, 6 H, N(CH
3 2
) ).
1
3
1
13
1
H), 1.34 (m, 1 H). C{ H}NMR (100 MHz, CDCl
1
1
3
) δ
75.0 (Cq, C=O), 144.0, 140.5 and 138.5 (Cq), 128.9,
28.6, 127.2, 126.6 and 126.5 (aromatic CH), 57.8
N(CH ), 46.7 ((C=O)CHCH), 44.3 ((C=O)CHCH),
3.4 (N(CH ), 34.4 (NHCH ), 29.2, 26.6, 25.7 and 21.7
3
) δ 171.5 (Cq, C=O),
2
2
(
CH
2
3
)
2
3
)
2
2
4
3
)
2
2
29.3 (cyclobutyl CH). HRMS Calcd for C33
[M+H] : 475.2749; Found: 475.2751.
H
34
N
2
O
+
+
(
cyclohexyl CH). HRMS Calcd for C23
H
30
N
2
O [M+H] :
3
51.2436; Found: 351.2436.
(
3S,4aR,6aR,6bS,8aS,11S,12aS,14aR,14bS)-11-([1,1'-
2
-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-
biphenyl]-4-ylmethyl)-11-((2-(dimethylamino)ethyl)-
cyclopropanecarboxamide (4l): 50 mg, 54% yield,
carbamoyl)-4,4,6a,6b,8a,14b-hexamethyl-14-oxo-1,2,3,4,
4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahy-
yellow liquid. The coupling constants of the proton NMR
1
spectrum suggest that 4l is the cis-diastereomer. H NMR
dropicen-3-yl acetate (4n): 89 mg, 40% yield, yellow
1
(
400 MHz, CDCl
3
) δ 7.84 (br s, 1 H, NH), 7.54 (d, J = 7.7
liquid. H NMR (400 MHz, CDCl
3
) δ 7.73 (m, 1 H, NH),
Hz, 2 H, aromatic CH), 7.48 (d, J = 8.1 Hz, 2 H), aromatic
CH, 7.39 (m, 4 H, aromatic CH), 7.30 (t, J = 7.3 Hz, 1 H,
7.58 (d, J = 7.3 Hz, 2 H, aromatic CH), 7.50 (d, J = 8.1 Hz,
2 H, aromatic CH), 7.42 (t, J = 7.6 Hz, 2 H, aromatic CH),
7.32 (t, J = 7.3 Hz, 1 H, aromatic CH), 7.20 (d, J = 8.1 Hz,
aromatic CH), 3.49 (m, 1 H, NHCH
NHCH ), 2.83 and 2.9 (m each, 1:1 H, CH
H, N(CH and cyclopropyl CH), 2.12, 1.80 and 1.30 (m
each, 1:1:1 H, cyclopropyl CH). C{ H}NMR (100 MHz,
CDCl ) δ 170.6 (Cq, C=O), 140.8, 139.0 and 136.5 (Cq),
29.8, 128.9, 127.2, 126.8 and 126.4 (aromatic CH), 58.1
CH NMe ), 43.6 (N(CH ), 34.9 (NHCH ), 24.6, 24.1
and 9.9 (cyclopropyl CH). HRMS Calcd for C20
2
), 3.34 (m, 1 H,
2
2
NMe
2
), 2.51 (m, 2 H, aromatic CH), 5.70 (s, 1 H, CH=C), 4.51 (dd, J = 11.5
and 4.9 Hz, 1 H, CO CH), 3.65, 3.03, 2.88, 2.77, 2.08, 1.66,
1.36 and 1.10 (m each, 2:2:7:6:9:10:8 H, alkyl CH, CH
and CH ), 2.36 (s, 1 H, CH) 0.87 (s, 6 H, CH ), 0.77 (s, 3
) δ 200.3 (C=O),
176.0 (CONH), 171.2 (CH=C), 169.3 (CO ), 140.7, 139.4,
136.1, 128.6 and 127.4 (Cq), 131.1, 128.9, 127.0 and 126.7
(aromatic CH and COCH), 80.8 (CO CH), 61.8
CHCOCHC), 58.9 (CH N(CH ), 55.1, 48.8, 48.0, 47.6,
5.5, 43.7, 43.3, 39.1, 38.9, 38.1, 37.5, 37.0, 34.6, 32.8,
2.0, 29.8, 28.7, 28.3, 28.2, 26.4, 23.7, 23.3, 21.4, 18.8,
7.5, 16.8 and 16.5 (Cq, CH, CH and CH ). HRMS Calcd
[M+H] : 735.5101; Found: 735.5101.
7
3
)
2
2
1
3
1
2
3
3
3
13
1
1
(
3 3
H, CH ). C{ H}NMR (100 MHz, CDCl
2
2
3
)
2
2
2
24 2
H N O
+
[
M+H] : 309.1967; Found: 309.1967.
2
(
2
3 2
)
2
,3-di([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)-
ethyl)cyclopropanecarboxamide (4l): 28 mg, 20% yield,
yellow solid, 108-109 C. H NMR (400 MHz, CDCl
.49 (d, J = 7.5 Hz, 5 H, aromatic CH), 7.37 (d, J = 8.2 Hz,
H, aromatic CH), 7.32 (d, J = 7.7 Hz, 3 H, aromatic CH),
.22 (m, 7 H, aromatic CH), 3.30 (q, J = 5.3 Hz, 2 H,
4
3
1
o
1
3
) δ
2
3
7
4
7
+
66 2 4
for C48H N O
(1S,4aR,4bR,10aR)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(2-
(dimethylamino)ethyl)-7-isopropyl-4a-methyl-1,2,3,4,
4a,4b,5,6,10,10a-decahydrophenanthrene-1-carboxa-
NHCH
2
), 2.89 (d, J = 9.4 Hz, 2 H, cyclopropyl CH), 2.47
m, 3 H, cyclopropyl CH and CH NMe ), 2.19 (s, 6 H,
). C{ H}NMR (100 MHz, CDCl ) δ 169.1 (Cq,
(
2
2
13
1
1
N(CH
3
)
2
3
mide (4o): 80 mg, 50% yield, yellow liquid. H NMR (400
C=O), 141.0, 139.0 and 134.1 (Cq), 131.6, 128.8, 127.2,
27.0 and 126.1 (aromatic CH), 58.1 (CH NMe ), 44.2
N(CH ), 35.6 (NHCH ), 28.3 and 28.2 (cyclopropyl CH).
HRMS Calcd for C32
MHz, CDCl
aromatic CH and NH), 5.77 (s, 1 H, CCHCH
H, CCHC), 3.54 (m, 3 H, NHCH and CH ), 3.00, 2.83,
2.40, 2.09, 2.00, 1.90, 1.80, 1.70 and 1.27 (m each,
1:3:1:2:2:1:2:2:4 H, CH, CH and CH ), 2.47 (s, 6 H,
N(CH ) 1.01 (m, 9 H, CH(CH and CH
100 MHz, CDCl ) δ 176.7 (Cq, C=O), 145.5 (Cq,
CCH(CH ), 140.9, 138.7, 138.6 and 135.5 (Cq), 131.7,
28.9, 127.2, 126.9 and 126.5 (aromatic CH), 122.3 and
21.1 (CH), 59.1 (CH N(CH ), 51.4, 51.3, 48.1, 44.4,
8.6, 36.1, 35.5, 35.0, 34.0, 31.3, 27.5, 25.2, 22.7, 21.5,
0.9, 18.4, 15.4 (Cq, CH, CH and CH ). HRMS Calcd for
O [M+H] : 525.3845; Found: 525.3845.
3
) δ 7.54, 7.42 and 7.31 (m each, 2:5:3 H,
1
(
2
2
2
), 5.42 (m, 1
3
)
2
2
2
2
+
32 2
H N O [M+H] : 461.2593; Found:
4
61.2593.
2
3
13
1
3
)
2
3
)
2
3
). C{ H}NMR
2
-([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)ethyl)-
(
3
cyclobutanecarboxamide (4m): 60 mg, 62% yield,
3 2
)
yellow liquid. The coupling constants of the proton NMR
1
1
3
2
1
spectrum suggest that 4m is the cis-diastereomer. H NMR
2
3 2
)
(
3
400 MHz, CDCl ) δ 7.51 (t, J = 8.1 Hz, 4 H, aromatic
CH), 7.37 (m, 4 H, aromatic CH), 7.29 (t, J = 7.3 Hz, 1 H,
aromatic CH), 6.74 (br s, 1 H, NH), 3.95 (q, J = 8.9 Hz, 1
2
3
+
36 48 2
C H N
H, (C=O)CHCH), 3.43 (m, 1 H, NHCH
2
), 3.20 and 3.08,
), 2.61 (m, 1 H, NHCH ), 2.39
m, 2 H, cyclobutyl CH), 2.20 (m, 9 H, N(CH and
) δ 173.0
Cq, C=O), 140.6, 140.5 and 140.0 (Cq), 128.8, 128.4,
(
(
m each, 1:1 H, CH
2
NMe
2
2
(1R,4aS,10aR)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(2-
(dimethylamino)ethyl)-7-isopropyl-4a-methyl-1,2,3,4,4a,
9,10,10a-octahydrophenanthrene-1-carboxamide (4p):
3 2
)
1
3
1
cyclobutyl CH). C{ H}NMR (100 MHz, CDCl
3
o
1
(
80 mg, 50% yield, white solid, m.p.: 124-125 C. H NMR
(400 MHz, CDCl ) δ 7.55 (d, J = 7.6 Hz, 2 H, aromatic
1
4
3
27.2, 126.7 and 126.5 (aromatic CH), 57.6 (CH
6.0 ((C=O)CHCH), 43.8 (N(CH ), 42.6 ((C=O)CHCH),
5.1 (NHCH ), 24.9 and 20.0 (cyclobutyl CH). HRMS
2
NMe
2
),
3
3
)
2
CH), 7.44 and 7.32 (m each, 4:4 H, aromatic CH), 7.17 (d,
J = 8.2 Hz, 1 H, aromatic CH), 6.99 (d, J = 7.9 Hz, 1 H,
aromatic CH), 6.88 (s, 1 H, NH), 3.60 (m, 1 H), 3.45 (d, J
2
+
Calcd for C21
26 2
H N O [M+H] : 323.2123; Found: 323.2122.
=
1
(
13.7 Hz, 2 H), 3.07 (d, J = 13.7 Hz, 1 H), 2.93 (dd, J =
7.2 and 6.4 Hz, 1 H), 2.80 (m, 4 H), 2.43 (m, 8 H), 1.95
m, 5 H), 1.66 (m, 2 H), 1.40 (s, 3 H), 1.22 (d, J = 6.9 Hz,
2
,4-di([1,1'-biphenyl]-4-yl)-N-(2-(dimethylamino)-
ethyl)cyclobutanecarboxamide (4m): 37 mg, 26% yield,
white solid, m.p.: 110-111 C. H NMR (400 MHz, CDCl )
3
o
1
1
1
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201801022
1
3
1
6
1
1
H). C{ H}NMR (100 MHz, CDCl
3
) δ 176.7 (Cq, C=O),
on silica gel (eluent: CH
compound 8.
2
Cl
2
/MeOH = 80:1, v/v) to afford
47.3, 145.9, 140.8, 138.8, 138.6 and 134.7 (Cq), 131.7,
28.9, 127.3, 126.9, 126.8, 126.5, 124.1 and 124.0
(
3
aromatic CH), 58.6, 51.8, 47.7, 44.2, 38.3, 35.5, 34.2, 33.5, N-(2-(dimethylamino)ethyl)-2-methyl-6-((triisopropyl-
1.4, 30.2, 26.6, 24.1, 19.9, 18.8 and 14.9 (Cq, CH, CH
2
silyl)ethynyl)benzamide (8): 107 mg, 92% yield, white
+
1
and CH
Found: 523.3687.
3 46 2
). HRMS Calcd for C36H N O [M+H] : 523.3688;
solid. H NMR (400 MHz, CDCl
H, aromatic CH), 7.15 (m, 2 H. aromatic CH), 6.28 (s, 1 H,
NH), 3.50 (dd, J = 11.4, 5.9 Hz, 2 H, CH NH), 2.48 (t, J =
6.1 Hz, 2 H, CH NMe ), 2.32 (s, 3 H, Me), 2.21 (s, 6 H,
NMe ), 1.10 (s, 21 H, Pr
CDCl ) δ 168.7 (Cq, C=O), 140.1, 135.2, 120.7, 104.7 and
4.1 (Cq) 130.6, 130.4 and 128.5 (aromatic CH), , 57.8
3
) δ 7.32 (d, J = 7.4 Hz, 1
2
N-(2-(dimethylamino)ethyl)-3-phenylpropanamide (4q):
1
2
2
5
3 mg, 80% yield, yellow liquid. H NMR (400 MHz,
CDCl ) δ 7.15 (m, 5 H, aromatic CH), 6.21 (s, 1 H, NH),
.19 (m, 2 H, NHCH ), 2.87 (t, J = 7.4 Hz, 2 H, CH Ph),
.44 – 2.35 (t, J = 7.5 Hz, 2 H, CH NMe ), 2.24 (t, J = 6.0
), 2.08 (s, 6 H, NMe
) δ 172.3 (Cq, C=O), 140.9 (Cq), 128.4, 128.3
and 126.1 (aromatic CH), 57.8 (CH NMe ), 45.0 (NMe ),
8.3 (NHCH ), 36.7 (COCH ), 31.7 (CH Ph). HRMS
Calcd for C13 O [M+H] : 221.1654; Found: 221.1655.
i
13
1
2
3
Si). C{ H}NMR (100 MHz,
3
3
3
2
2
2
9
2
2
3
1
1
(CH NMe ), 45.2 (NMe ), 37.20 (NHCH ), 19.3 (Me),
Hz, 2 H, COCH
MHz, CDCl
2
2
). C{ H}NMR (100
2
2
2
2
1
8.78 (Si(CH(CH
3
)
2
)), 11.4 (Si(CH(CH
3
)
2
)). HRMS Calcd
3
+
for C23
H
38
N
2
OSi [M+H] : 387.2832; Found: 387.2833.
2
2
2
3
2
2
2
+
H
20
N
2
General procedure for the synthesis of 2-arylated
benzamide derivatives 9
General procedure for the synthesis of (S)-N-(2-
(
(
dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-2-yl)-5-
triisopropylsilyl)pent-4-ynamide (6)
Under an air atmosphere a mixture of benzamide 7a or 7b
(0.3 mmol), 4-iodobiphenyl (2p) (126 mg, 0.45 mmol),
2 2 3
Pd(TFA) (10 mg, 0.03 mmol), and Ag CO (66 mg, 0.24
o
Under an air atmosphere
dimethylamino)ethyl)-2-(1,3-dioxoiso-indolin-2-yl)pro-
panamide (1a) (87 mg, 0.3 mmol), (bromoethynyl)-tri-iso-
propylsilane (5) (117 mg, 0.45 mmol), Pd(TFA) (10 mg,
.03 mmol), and Ag CO (66 mg, 0.24 mmol) in 1.5 mL
tAmOH was stirred at 60 C for 24 hours. After cooled to
ambient temperature, the reaction mixture was filtered
through a short pad of celite. The filtrate was concentrated
in vacuo, and the resulting residue was subjected to
purification by column chromatography on silica gel
a
mixture of N-(2-
mmol) in 1.5 mL tAmOH was stirred at 110 C for 48
hours. After cooled to ambient temperature, the reaction
mixture was filtered through a short pad of celite. The
filtrate was concentrated in vacuo, and the resulting residue
was subjected to purification by column chromatography
(
2
0
2
3
o
on silica gel (eluent: CH
the target product 9a or 9b.
2 2
Cl /MeOH = 70:1, v/v) to afford
N-(2-(dimethylamino)ethyl)-3-methyl-[1,1':4',1''-ter-
phenyl]-2-carboxamide (9a): 72 mg, 67% yield, yellow
o
1
solid, m.p.: 185-186 C. H NMR (400 MHz, CDCl
.58 and 7.32 (m each, 6:3 H, aromatic CH and NH), 7.43
t, J = 7.6 Hz, 2 H, aromatic CH), 7.18 (d, J = 7.9 Hz, 2 H,
aromatic CH), 3.53 (q, J = 5.6 Hz, 2 H, NHCH ), 2.59 (t, J
5.5 Hz, 2H, CH N(CH ), 2.34 (d, J = 9.2 Hz, 9 H,
). C{ H}NMR (100 MHz, CDCl ) δ
70.6 (Cq, C=O), 140.2, 140.1, 139.9, 138.7, 135.9 and
35.2 (Cq), 57.7 (CH N(CH ), 43.5 (N(CH ), 34.9
), 19.5 (CH ). HRMS Calcd for C24
M+H] : 359.2123; Found: 359.2124.
3
) δ
(
eluent: CH
2 2
Cl /MeOH = 80:1, v/v) to afford the target
7
(
product 6.
(
S)-N-(2-(dimethylamino)ethyl)-2-(1,3-dioxoisoindolin-
2
2
-yl)-5-(triisopropylsilyl)pent-4-ynamide (6): 85 mg,
=
2
3 2
)
o
1
6
0% yield, white solid, m.p.: 152-153 C. H NMR (400
) δ 7.86 and 7.73 (m each, 2:2 H, aromatic
CH), 6.71 (brs, 1 H, NH), 5.01 (dd, J = 10.9 and 5.7 Hz, 1
13
1
N(CH
3
)
2
and CH
3
3
MHz, CDCl
3
1
1
2
3
)
2
3 2
)
H, CH), 3.34 (m, 3 H, NHCH
7.3 and 5.7 Hz, 1 H, CHCH
CH NMe
2
and CHCH
), 2.39 (t, J = 6.1 Hz, 2 H,
2
), 3.14 (dd, J =
(
[
NHCH
2
+
3
26 2
H N O
1
2
i
2
2
), 2.16 (s, 6 H, NMe
C{ H}NMR (100 MHz, CDCl
C=O), 134.3 and 123.6 (aromatic CH), 132.0 (Cq), 103.3
and 83.9 (alkynyl C), 57.8 (CH NMe ), 52.8 (CHCH ),
5.2 (NMe ), 37.2 (NHCH ), 20.8 (CHCH ), 18.4
CHCH ), 11.1 (CHCH ). HRMS Calcd for C26 Si
M+H] : 470.2839; Found: 470.2835.
2
), 0.83 (m, 21 H, Si( Pr)
3
).
13
1
N-(2-(dimethylamino)ethyl)-[1,1':4',1''-terphenyl]-2-
carboxamide (9b): 67 mg, 65% yield, white solid, m.p.:
3
) δ 167.7 and 167.5 (Cq,
o
1
98-99 C. H NMR (400 MHz, CDCl
7.35 (m each, 5:6:3 H, aromatic CH and NH), 3.53 (q, J =
5.3 Hz, 2 H, NHCH ), 2.80 (t, J = 5.6 Hz, 2 H,
CH N(CH ), 2.45 (s, 6 H, N(CH
MHz, CDCl ) δ 170.6 (Cq, C=O), 140.3, 140.1, 139.6,
3
) δ 7.58, 7.44 and
2
2
2
4
2
2
2
(
[
3
+
3
H
39
N
3
O
3
2
13
1
2
3
)
2
3 2
) ). C{ H}NMR (100
3
General procedure for the synthesis of N-(2-
dimethylamino)ethyl)-2-methyl-6-((triisopropylsilyl)-
139.5 and 135.4 (Cq), 130.4, 130.2, 129.5, 129.0, 128.2,
127.6, 127.5, 127.0 and 126.9 (aromatic CH), 57.4
(
ethynyl)benzamide (8)
(CH
Calcd for C23
2
N(CH
3
)
2
), 43.6 (N(CH
H N O [M+H] : 345.1967; Found: 345.1968.
24 2
3
+
)
2
), 35.3 (NHCH
2
). HRMS
Under an air atmosphere a mixture of N-(2-(dimethyl-
amino)ethyl)-2-methylbenzamide (7a) (62 mg, 0.3 mmol),
General procedure for the removal of the diamine
auxiliary
(
bromoethynyl)-tri-iso- propylsilane (5) (117 mg, 0.45
mmol), Pd(TFA) (10 mg, 0.03 mmol), and Ag CO (66
2
2
3
o
mg, 0.24 mmol) in 1.5 mL tAmOH was stirred at 110 C
for 36 h. After cooled to ambient temperature, the reaction
mixture was filtered through a short pad of celite. The
filtrate was concentrated in vacuo, and the resulting residue
was subjected to purification by column chromatography
A mixture of arylated aliphatic acid derivatives (3) (0.3
3 2
mmol), BF OEt (0.426 g, 3.0 mmol), and 2 mL methanol
was stirred at 110 °C for 20 hours in a 10-mL screw-
capped glass tube. After cooled to ambient temperature,
3
Et N (0.461 g, 4.6 mmol) was added to the reaction
1
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
mixture with stirring. All the volatiles were removed under
reduced pressure, and the resultant residue was subjected
44, 2112–2115.
[4] V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem.
Soc. 2005, 127, 13154–13155.
to purification by flash chromatography on silica gel
o
[
5] a) D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010,
32, 3965–3972; b) L. D. Tran, O. Daugulis, Angew.
(
eluent: petroleum ether (60-90 C)/ethyl acetate = 10:1,
1
v/v) to afford the target product 10.
Chem. Int. Ed. 2012, 51, 5188–5191; c) R. Shang, L.
Ilies, A. Matsumoto, E. Nakamura, J. Am. Chem. Soc.
(
S)-methyl 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropa-
noate (10a): 75 mg, 80% yield, yellow solid, m.p.: 83-84
2
013, 135, 6030–6032; d) X. S. Wu, Y. Zhao, H. B. Ge,
o
20
1
C, 98% ee, [α]
400 MHz, CDCl
D
= -195.24 (c 0.40, CHCl
3
). H NMR
Chem. Sci. 2015, 6, 5978–5983; d) P. X. Ling, S. L.
Fang, X. S. Yin, Q. Zhang, K. Chen, B. F. Shi, Chem.
Commun. 2017, 53, 6351–6354.
(
3
) δ 7.75, 7.64 and 7.15 (m each, 2:2:5 H,
aromatic CH), 5.17 (dd, J = 11.2 and 5.3 Hz, 1 H, CH),
1
3
1
3
.76 (s, 3 H, CH
MHz, CDCl ) δ 169.3 and 167.4 (Cq, C=O), 136.7 and
31.5 (Cq), 134.1, 128.8, 128.5, 126.8 and 123.4 (aromatic
CH), 53.2 (CH), 52.9 (CH ), 34.6 (CH ). HRMS Calcd for
[M+H] : 310.1079; Found: 310.1077. HPLC
OD-H column, hexane/iPrOH 70:30, 0.8 mL/min, 210
nm) t = 10.1 min, t = 11.5 min (major).
3
), 3.57 (m, 2 H, CH
2
). C{ H}NMR (100
[6] a) W. R. Gutekunst, R. Gianatassio, P. S. Baran, Angew.
Chem. Int. Ed. 2012, 51, 7507–7510; b) B. Wang, C. X.
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Earsad, A. Hazra, D. Maiti, Chem.-Eur. J. 2015, 21,
3
1
3
2
+
18 4
C H15NO
(
1
1320–11324; d) C. Lin, Z. K. Chen, Z. X. Liu, Y. H.
Zhang, Org. Lett. 2017, 19, 850–853.
1
2
[
7] a) S. Y. Zhang, Q. Li, G. He, W. A. Nack, G. Chen, J.
Am. Chem. Soc. 2013, 135, 12135–12141; b) K. Chen,
B. F. Shi, Angew. Chem. Int. Ed. 2014, 53, 11950–
11954; c) X. S. Wu, Y. Zhao, H. B. Ge, J. Am. Chem.
Soc. 2014, 136, 1789–1792; d) Z. Z. Zhang, Y. Q. Han.
B. B. Zhan, S. Wang, B. F. Shi, Angew. Chem. Int. Ed.
2017, 56, 13145–13149.
(
S)-methyl 2-(1,3-dioxoisoindolin-2-yl)-3-(4-methoxy-
phenyl)propanoate (10b): 74 mg, 72% yield, white solid,
o
1
m.p.: 132-133 C. H NMR (400 MHz, CDCl
.66 (m each, 2:2 H, aromatic CH), 7.05 (d, J = 8.5 Hz, 2
H, aromatic CH), 6.69 (d, J = 8.6 Hz, 2 H, aromatic CH),
3
) δ 7.75 and
7
5
3
.10 (dd, J = 11.0 and 5.6 Hz, 1 H, CH), 3.75 (s, 3 H, CH
.67 (s, 3 H, CH ), 3.51 (m, 2 H, CH
3 2
3
),
). C{ H}NMR (100
) δ 169.4 and 167.5 (Cq, C=O), 158.4, 131.6
and 128.7 (Cq), 134.1, 129.8, 123.5 and 114.0 (aromatic
CH), 55.1 (CH), 53.4 and 52.9 (CH ), 33.8 (CH ). HRMS
[M+H] : 340.1185; Found: 340.1184.
1
3
1
[
8] a) Y. Ano, M. Tobisu, N. Chatani, J. Am. Chem. Soc.
2
011, 133, 12984–12986; b) J. T. Zhang, H. Chen, C.
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3
Lin, Z. X. Liu, C. Wang, Y. H. Zhang, J. Am. Chem.
Soc. 2015, 137, 12990–12996; c) F. X. Luo, Z. C. Cao,
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3
2
+
Calcd for C19
H17NO
5
methyl 3-([1,1'-biphenyl]-4-yl)propanoate (10c): 58 mg,
[9] a) G. Shan, X. L. Yang, Y. Zong, Y. Rao, Angew.
Chem. Int. Ed. 2013, 52, 13606–13610; b) Z. Wang, Y.
Kuninobu, M. Kanai, Org. Lett. 2014, 16, 4790–4793;
c) K. Chen, S. Q. Zhang, H. Z. Jiang, J. W. Xu, B. F.
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1
8
7
0% yield, white solid. H NMR (400 MHz, CDCl
.45 and 7.33 (m each, 4:2:3 H, aromatic CH), 3.71 (s, 3 H,
CH CO Me), 2.69 (t, J
Me). C{ H}NMR (100 MHz,
) δ 173.4 (Cq, C=O), 141.0, 139.7 and 139.4 (Cq),
28.9, 128.8, 127.4, 127.3 and 127.1 (aromatic CH), 51.7
OMe), 35.7 (CH COMe), 30.7 (CH CH COMe). HRMS
Calcd for C16 [M+H] : 241.1229; Found: 241,1226.
3
) δ 7.57,
OMe), 3.02 (t, J = 7.8 Hz, 2 H, CH
2
2
2
1
3
1
=
7.8 Hz, 2 H, CH
2 2 2
CH CO
CDCl
1
(
3
2
015, 17, 2768–2771.
[
10] a) Z. Wang, J. Z. Ni, Y. Kuninobu, M. Kanai, Angew.
Chem. Int. Ed. 2014, 53, 3496–3499; b) X. S. Wu, K.
Yang, Y. Zhao, H. Sun, G. G. Li, H. B. Ge, Nat.
Commun. 2015, 6, 6462.
2
2
2
+
16 2
H O
[
11] a) X. S. Wu, Y. Zhao, H. Ge, J. Am. Chem. Soc. 2015,
Acknowledgements
1
37, 4924–4927; b) G. Liao, X. S. Yin, K. Chen, Q.
Zhang, S. Q. Zhang, B. F. Shi, Nat. Commun. 2016, 7,
2901; c) P. Williamson, A. Galván, M. J. Gaunt,
We are grateful to the National Natural Science
Foundation of China (21472185 and 21871253) and the
1
Chem Sci. 2017, 8, 2588–2591.
National
Basic
Research
Program
of
China
[
12] a) Y. J. Liu, Y. H. Liu, Z. Z. Zhang, S. Y. Yan, K.
(2015CB856600) for support of this research.
Chen, B. F. Shi, Angew. Chem. Int. Ed. 2016, 55,
1
3859–13862; b) X. L. Yang, Y. H. Sun, T. Y. Sun,
Y. Rao, Chem. Commun. 2016, 52, 6423–6426.
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Advanced Synthesis & Catalysis
10.1002/adsc.201801022
FULL PAPER
A Simple Aliphatic Diamine Auxiliary for
Palladium-Catalyzed Arylation of Unactivated β-
3
C(sp )H Bonds
Adv. Synth. Catal. Year, Volume, Page – Page
Jiang Lou, Quannan Wang, Yuan He, and
Zhengkun Yu*
1
5
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