Palladium-catalyzed oxalyl amide assisted direct ortho-alkynylation of arylalkylamine derivatives at δ and ε positions

Article abstract of DOI:10.1039/c5cc04390e

Palladium-catalyzed oxalyl amide directed ortho-alkynylation of arylalkylamine derivatives is reported for the first time. A wide variety of β-arylethamine and γ-arylpropamine derivatives are compatible with this protocol. This method provides a general means to synthesize substituted alkynylarylalkylamine derivatives, highlighting the ability of oxalyl amide in promoting C-H functionalization at unique δ and ε positions.

Full text of DOI:10.1039/c5cc04390e

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DOI: 10.1039/C5CC04390E
Journal Name
COMMUNICATION
Palladium-Catalyzed Oxalyl Amide Assisted Direct ortho-
Alkynylation of Arylalkylamines Derivatives at δ and ε Positions
Mingyu Guan,a Changpeng Chen,a Jingyu Zhang,b Runsheng Zeng*a and Yingsheng Zhao*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Palladium-catalyzed oxalyl amide directed ortho-alkynylation of assisted ortho-alkynylation of aromatic carboxylic acid derivatives.23
arylalkylamine derivatives is first reported. A wide variety of β- In 2014, Yu and coworkers reported from their seminal work a
arylethamine and γ-arylpropamine derivatives are compatible copper-catalyzed alkynylation of aryl C–H bonds with alkyne in good
with this protocol. The method provides a general means to yields.24 Very recently, Shi and co-workers developed the oxidative
synthesize
substituted
alkynylarylalkylamine
derivatives, ethynylation of (hetero)aryl C–H bonds in the presence of catalyst
highlighting the ability of oxalyl amide in promoting C–H by using an auxiliary agent, 2-(pyridin-2-yl)isopropylamine.25
functionalization at unique δ and ε positions.
Despite significant progress in the realization of ortho-alkynylation
of β-arylethamine and γ-arylpropamine derivatives, there are still
no reports on this reaction. Herein, we report the palladium-
catalyzed selective functionalization of ortho C–H bonds of
arylalkylamine oxalyl amide derivatives with acetylenic bromide via
a six- or seven-membered palladacycle intermediate.
Alkynes are special building blocks in synthetic chemistry and in
materials chemistry because of their versatile transformation into
multiple functional groups or linear structure motifs.1 One of the
most convenient methods for adding alkyne functionality is
transition-metal-catalyzed Sonogashira–Hagihara coupling reaction
combining aryl halide with terminal alkynes.2 In recent years,
Scheme 1 Synthesis of Aryl Alkynes by Transition-Metal-Catalyzed
transition-metal-catalyzed direct C–H functionalization reactions C–H Alkynylation.
have become a rapidly expanding area in synthetic chemistry.3
Oxidative coupling of C–H bonds with alkynyl halides, hypervalent
iodine, or terminal alkynes has been developed in various studies.
In 2007, Gevorgyan and co-workers reported a seminal example of
palladium-catalyzed C–H alkynylation of electron-rich heterocycles
with alkynyl halides, which represents a new approach for C(sp2)–
C(sp) bond formation.4 Since this work, groups of Chatani,5 Miura,6
Su,7 Chang,8 Gevorgyan,9 Li,10 Loh,11 Shi,12 and others13 expanded
oxidative alkynylation to various C–H bonds with alkyne in the
presence of transition-metal catalyst or alkyne reagents (Scheme
1A). Additionally, the well-developed bidentated directing group
strategy14-21 has also well applied in the oxidative alkynylation
reactions. For example, Chen and co-workers reported
picolinamide-promoted palladium-catalyzed ortho-alkynylation of
benzylamine substrates with acetylenic bromide with high yields in
With these considerations in mind, we initially treated oxalyl
2012 (Scheme 1B).22 Later, Chatani described the 8-aminoquinoline
amide protected 1a with bromoalkyne 2 in the presence of
Pd(OAc)2, stoichiometric AgOAc, pivalicacid, and toluene under
aerobic conditions at 100 oC for 24 h. The desired alkynylated
products 3a was obtained at 67% yield (Table 1, entry 1). Upon
further evaluation of the reaction conditions, we discovered that
only acetic salt could be employed to instead of expensive silver salt
in promoting this palladium-catalyzed oxalyl amide assisted
alkynylation reaction. Among the acetic acid salts tested, CsOAc
a.Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry,
Chemical Engineering and Materials Science Soochow University, Suzhou 215123,
China.Email: yszhao@suda.edu.cn; zengrunsheng@suda.edu.cn.
b.College of Physics, Optoelectronics and Energy & Collaborative Innovation Center
of Suzhou Nano Science and Technology, Soochow University, Suzhou 215006,
China. Email: jyzhang@suda.edu.cn.
† Electronic Supplementary Informaꢀon (ESI) available: Detailed experimental
procedures and characterization data. See DOI: 10.1039/x0xx00000x
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Table 1 Optimization of Reaction Conditionsa
emerged as the best additive, as it produced 3a in 93% yield. We
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DOI: 10.1039/C5CC04390E
hypothesized that the acetate ion might act as a proton shuttle
during the catalytic cycle, as reported by Larock and Fagnou;
meanwhile, cesium ion behaved as a base by keeping the reaction
in an alkaline environment. Several other bases such as K2CO3,
KHCO3, and Na2CO3 combined with pivalic acid were also screened;
all tests afforded results slightly poorer than those of CsOAc.
Control experiments revealed that the palladium catalyst was
crucial for this alkynylation reaction (Table 1, entry 12).
Entry
1
Pd(OAc)2
(mol %)
Base
_
Additive
Yield
(%)
(equiv)
AgOAc (2)
5
67
PivOH (0.3)
Table
3 Palladium-Catalyzed Oxalyl Amide Directed ortho-
Alkynylation of γ-Arylpropamine Derivativesa
2
3
5
5
5
5
5
5
5
5
5
5
_
LiOAc
NaOAc
KOAc
_
4
31
_
X
OA
X
OA
Br
4
_
62
93(85b)
22
Pd(OAc)2
AgOAc, KOAc
N
H
N
R
H
R
5
CsOAc
Na2CO3
K2CO3
KHCO3
Na2CO3
K2CO3
CsOAc
CsOAc
_
toluene, Ar
H
X = CH2, O
4
TIPS
O
120 oC, 36 h
6
_
TIPS
2
F
5
7
_
36
OMe
Cl
8
_
56
O
OA
OA
O
OA
N
N
H
N
H
9
PivOH (0.3)
PivOH (0.3)
PivOH (0.3)
_
47
H
10
11
12
36
TIPS
TIPS
TIPS
5c
, 66%
5a, 84%
5b
, 60%
51
Me
O
NR
Me
OA
O
OA
Cl
O
OA
N
H
N
H
N
H
aReaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), Pd(OAc)2
(5 mol %), base (2 equiv), toluene (0.5 mL), 100 C, air, 24 h.
o
TIPS
TIPS
TIPS
5f
, 67%
5e, 58%
5d, 72%
Yield was based on LC using acetophenone as the internal
CO2Me
standard. bIsolated yield at 0.2 mmol scale.
o'
o'
OA
OA
N
H
N
H
OA
o
o
N
H
MeO
Table
2 Palladium-Catalyzed Oxalyl Amide Directed ortho-
Alkynylation of Phenylethylamine Derivativesa
TIPS
TIPS
5i
mono, 45%
5h
mono, 47%
5h( ')di, 28%
TIPS
5g
, 91%
5i(o+o')di, 33%
o+o
aReaction conditions: 4 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (5
mol %), AgOAc (2.0 equiv), KOAc (3.0 equiv), toluene (1 mL), Ar, 120
oC, 36h. Isolated yields.
With these optimized conditions, we proceeded to explore the
substrate scope. Representative data for this study were shown in
Table 2. Generally, both electron-donating and electron-
withdrawing functional groups substituted oxalyl amide protected
phenylethylamine derivatives in the reaction afforded the
corresponding products in good to excellent yields. Various
functional groups such as F, Cl, Br, CF3, NO2, Me, and OMe were
compatible in this oxalyl amide assisted C–H transformation. Para-
substituted substrates (1g–1i) gave a mixture of mono- and
dialkynylated products at a ratio of 2:1 to 3:1 in good yields, which
could be easily separated by silica gelchromatography (Table 2, 3g–
3i). Substitution of functional groups of CF3 at the meta-position
caused the alkynylation to favorless-hindered positions, resulting in
mono-alkynylated products in good to excellent yield. However, the
less steric functional group of Cl, Br, and MeO resulted in poor
selectivity at the ortho position (See Supporting Information).
Nevertheless, heterocycles were also tolerated in the reaction. For
example, oxalyl amide protected 2-thiopheneethylamine gave the
alkynylated product 3p in excellent yield. The tryptophan derivative
1q reacted with 2 at high temperature, selectively leading to 3q in
good yield. It is worth mentioning that palladium-catalyzed
aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (5
mol %), CsOAc (2 equiv), toluene (0.5 mL), 80 C, air, 24 h. Isolated
o
yields. b100 oC. c120 oC, 36h. d140 oC, 36h.
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alkynylation favored vinylic bonds (1r), affording the important nitrobenzenesulfonyl chloride and sodium hydride. Importantly, the
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synthons 1,3-enynes in good yield.
alkynylated β-arylethamine oxalyl amideDO3I:a10.c10o3u9ld/C5bCeC04e3a9s0ilEy
converted to the valuable synthon, dihydroisoquinoline derivative,
in good yield. The protecting group of TIPS could be readily
removed with TBAF to afford the terminal alkyne, which could
furnish a wide variety of alkynylated arylalkylamine derivatives.
In conclusion, we have developed palladium-catalyzed
alkynylation of arylalkylamine derivatives via rare six- and
seven-membered palladacycles using our developed oxalyl
amide directing group. A wide variety of β-arylethamine and γ-
arylpropamine derivatives are compatible with this synthetic
Scheme 2 Dialkynylation.
method, which provides
a general means to furnish
alkynylated arylalkylamines derivatives under mild conditions.
Direct conversion of the product to the useful synthetic
synthons isoquinoline derivatives highlights the potential
synthetic utility of this method.
Because of the successful alkynylation of β-arylethamine
We gratefully acknowledge financial support from the
derivatives, we then proceeded to explore the difficult ε-C(sp2)–H Natural Science Foundation of Jiangsu Province of China
alkynylation via a seven-membered palladacycle intermediate. (BK20130294), and the Young National Natural Science
Alkynylation of oxalyl amide protected γ-arylpropamine derivatives Foundation of China (No.21402133) for support of this work.
using silver acetate instead of cesium acetate proceeded slowly, The PAPD is also gratefully acknowledged.
affording the ε-alkynylated products in good yields (Table 3). The
substrates (Table 3, 4a–4i) also gave the ortho-alkynylated products
Notes and references
in moderate to good yields. Importantly, the steric effect in this
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