Oxalyl amide assisted palladium-catalyzed arylation of C(sp2)-H bond at the δ position

Article abstract of DOI:10.1021/ol502745g

A successful protocol has been developed for δ-arylation of β-arylethamines at the ortho position under mild conditions. The newly developed methodology first presents broad substrate scope, great functional group tolerance, and good to excellent yield in the synthesis of substituted β-arylethylamines. The transformation represents a practical advantage of oxalyl amide in assistance with C-H functionalization at a remote position.

Full text of DOI:10.1021/ol502745g

Letter
pubs.acs.org/OrgLett
Oxalyl Amide Assisted Palladium-Catalyzed Arylation of C(sp2)−H
Bond at the δ Position
Jian Han, Pei Liu, Chao Wang, Qian Wang, Jingyu Zhang, Yanwei Zhao, Daqing Shi, Zhibin Huang,*
and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: A successful protocol has been developed for δ-arylation of β-arylethamines at the ortho position under mild
conditions. The newly developed methodology first presents broad substrate scope, great functional group tolerance, and good to
excellent yield in the synthesis of substituted β-arylethylamines. The transformation represents a practical advantage of oxalyl
amide in assistance with C−H functionalization at a remote position.
workers reported the picolinamide-assisted γ-functionalization of
ransition-metal-catalyzed C−H bond activation for C−C
Tbond formation reactions has regained considerable natural amino acids in moderate yields.4 In 2013, N-(2-
pyridyl)sulfonyl-promoted γ-arylation of amino acid derivatives
at a high reaction temperature was reported by Carretero and co-
workers.5 Ma and Fan also developed a protocol for γ-arylation of
substituted 2-aminobutanates by employing 2-methoxyiminoa-
cetyl as the directing group with limited substrate scope.6
Interestingly, the palladium-catalyzed ortho trifluoromethylation
of N-unsubstituted benzyl amines could be directly achieved,
which was discoverd by the Yu group.7 Very recently, Yu and co-
workers also developed γ-arylation of C(sp3)−H bonds of triflyl-
protected amines with arylboron reagents through application of
mono-N-protected amino acid as a ligand.8
attention in the last decades and has become an efficient method
for synthesis of natural products and pharmaceutical agents.1
Among these reports, functionalization of directing-group-
containing arenes or unactivated C(sp3)−H bonds has been
extensively investigated.2 Especially in recent years, several
groups have demonstrated that amide groups possess a superior
ability to assist palladium-catalyzed regioselective functionaliza-
tion of C(sp2)−H or C(sp3)−H bonds.3 However, only a few
directing groups derived from amine derivatives were reported
(Scheme 1A). For example, Daugulis and co-workers first
discovered palladium-catalyzed γ-arylation of amine derivatives
by applying picolinamide as directing group. Later, Chen and co-
Although these directing groups had made a wide variety of
transformations and greatly enriched the reaction scope, these
auxilixary-promoted palladium-catalyzed C−C bond formation
reactions mostly go through a kinetically favored five-membered
palladcycle intermediate to achieve γ-arylation.9 To date, there
are few reports of directing group assisted selective δ- and ε-
arylation of amine derivatives which undergo a six- or seven-
membered palladacycle pathway.10 Herein, we reported an
efficient method for the arylation of δ-C(sp2)−H bonds of oxalyl
amide protected β-arylethamines with aryl iodides via six-
membered palladcycles. Our new methodology showed a wide
substrate scope and great functional group tolerance in the
synthesis of substituted β-arylethylamines under mild conditions,
which disclosed the super assistance ability of oxalyl amide at
remote position in C−H functionalization (Scheme 1B).
Scheme 1. Protecting Group Directed C−H Activation
The weak coordinating directing groups, such as carboxylic
acid,11 hydroxyl,12 methoxyl,13 and ketone14 could selectively
achieved different types of C−H functionalization. Generally,
Received: September 17, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Directing Group Optimization Studies
Table 2. Scope of Aryl Iodides Reagents for δ-C(sp2)−H
a
Arylation Reaction
a
Reaction conditions: 1g (0.2 mmol), ArI (0.3 mmol), Pd(OAc)2 (2.5
a
Reaction conditions: 1a−l (0.2 mmol), p-Tol-I (0.3 mmol),
Pd(OAc)2 (2.5 mol %), K2CO3 (0.4 mmol), PivOH (0.06 mmol),
DCE (0.3 mL), 80 °C, 24 h. Isolated yields.
mol %), K2CO3 (0.4 mmol), PivOH (0.06 mmol), DCE (0.3 mL), 80
°C, 24 h. Isolated yields. 100 °C. Ag2CO3 (0.2 mmol) was used
instead of K2CO3, 100 °C. Pd(OAc)2 (5 mol %), 100 °C.
b
c
d
these weak coordinating auxiliaries promoted C(sp2)−H
activation could selectively happened at δ positions. The δ-
alkenylation of the triflyl-protected β-arylethamine was also
developed by the Yu group in 2008.15 Very recently, oxalyl amide
was discovered as an easily accessible and efficient directing
group16 for selective C−H activation at δ or ε position by our
group. Inspired by the assistance ability of oxalyl amide, we
hypothesized that the new developed N,O-bidentated directing
group for amine derivatives might promote the selective arylation
of C(sp2)−H bonds at δ or ε position.
The phenylethylamine derivatives are important versatile
sythetic precursors.17 We first tested acetylated, triflated, and
picolinamide-protected phenylethylamine to realize arylation at
ortho position under various conditions. However, all failed to
give the arylated product in acceptable yield under mild
conditions (2a−c). We were pleased to find that the desired
arylated product was obtained in 15% yield by employing methyl
oxalyl ester (2d) as directing group, following Fagnou’s base
system,18 using Pd(OAc)2 (0.025 equiv), 4-iodotoluene (1.5
equiv), K2CO3 (2 equiv), PivOH (0.3 equiv), and DCE as
solvent at 80 °C. The catalytic amount of pivalic acid was
necessary for the transformation (for detailed optimal reaction
conditions, see the Supporting Information). It is suggested that
the pivalate anion acts as a proton shuttle between substrate and
inorganic base as disclosed by Larock and Fagnou.18 It is not
surprising that the ortho-arylated product 2e could be isolated in
72% yield when we applied oxalyl amide instead of ester. To
further understand the assistance ability of different amides, a
series of oxalyl amide protected phenylethylamines were
prepared and screened (Table 1, 2e−l). Generally, much better
yields were achieved when we applied oxalyl amide instead of
ester (2e−g). Diethylamine could increase the yield up to 81%
(2f). To our delight, compounds 1g give the corresponding
arylated product in best yield (2g). Further, when more bulky
secondary amine was applied, the yield dramatically decreased
(2h,i). Piperidine and morpholine were less active, and more
than 40% of starting material was recovered, respectively (2j,k).
tert-Butyl amine directly shut down the reaction as the strong
coordination to the palladium center (2l). Thus, we chose the
oxalyl amide, which was made from general reagents of
diisopropylamine and oxalyl chloride as the directing group to
test the scope of primary amines as arylation substrates.
Using the newly developed protocol, a broad range of aryl
iodides were successfully applied with substrate 1g as shown in
Table 2. Gratifyingly, the electron-withdrawing groups such as
Br-, I-, Ac-, CN-, NHAc-, CHO-, NO2-, and CF3-substituted
benzene iodides were tolerated in this transformation and gave
good to excellent yields. It is worth mentioning that even the
iodine substitution on the aromatic ring was achieved in 71%
yield by increasing the reaction temperature to 100 °C (3f). The
electron-rich aryl iodide also showed nice reactivity and gave
excellent yield (3k). To our interest, the pyridine substrate also
gave the arylated product 3l in 67% yield employing 5 mol % of
B
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a
palladium acetate at 100 °C. However, when we tried to use 4-
bromotoluene, just 15% yield of desired product was isolated
(Supporting Information).
Table 3. Substrate Scope of the β-Arylethyamines
We next moved our attention to other β-arylethyamines. Good
yields and high selectivity were observed for all of the substrates
under mild conditions (Table 3). The electronic factor had
nearly no effect on these arylation reactions at the δ position
(5a−i) except for the substrate (4f). However, substrates 4k−m
gave mono- and diarylated products without any selectivity when
K2CO3 (2 equiv), PivOH (0.3 equiv), and 4-iodotoluene (3
equiv) were used under palladium catalyst. When we applied
silver carbonate instead of potassium carbonate and pivalic acid,
satisfactory yields were obtained (5k−m), indicating the better
reactivity of silver carbonate than that of potassium carbonate
and pivalic acid catalyst system. High monoarylation took place
regioselectively at the less hindered site (5b,c,f,i,j). To the best of
our knowledge, selective arylation of amine derivatives at ε
position still has no reports. Delightedly, the substrate of 4n
could be arylated at the ε position in moderate yield via palladium
catalyst (5n).
The gram-scale reaction was successfully achieved with 0.5 mol
% of Pd(OAc)2 in 80% yield, which highlighted the power of this
approach (Scheme 2). The easily accessible and removable
ability was crucial for auxiliary in C−H activation.19 Notably, the
new developed directing group fulfilled these requirements. The
oxalyl amide could be easily prepared from diisopropylamine and
oxalyl chloride which are cheap and easily accessible reagents.
Besides, the oxalyl amide could be removed readily under mild
conditions in excellent yield (Scheme 2).
The ortho C−H bond of substrate 4h was deuterated under
the catalysis of Pd(OAc)2 in AcOD, giving compound [D]-4h in
92% yield.20 A primary kinetic isotope effect (∼2.9) was observed
under the general arylation conditions, implicating C−H
activation as the rate-determing step in the catalytic cycle
(Supporting Information).21
a
Reaction conditions: 4a−j (0.2 mmol), p-Tol-I (0.3 mmol),
Pd(OAc)2 (2.5 mol %), K2CO3 (0.4 mmol), PivOH (0.06 mmol),
DCE (0.3 mL), 80 °C, 24 h. Isolated yields. 100 °C. 120 °C. 4k−m
(0.2 mmol), p-Tol-I (0.6 mmol), Pd(OAc)2 (5 mol %), Ag2CO3 (0.3
mmol), 120 °C. 4n (0.2 mmol), p-Tol-I (0.3 mmol), Pd(OAc)2 (5
mol %), Ag2CO3 (0.3 mmol), 100 °C.
b
c
d
e
Scheme 2. Scale Up and Removal of the Directing Group
To further investigate the mechanism of arylation promoted
by oxalyl amide, substrate 4h with 2 equiv of acetonitrile and 1
equiv of Pd(OAc)2 in benzene-d6 at 80 °C was monitored at
different times. The results indicated that C−H activation can
take place without involvement of the ArI substrates (see the
Supporting Information). We then tried to get the six-membered
palladacycle intermediate in toluene and acetonitrile. Unfortu-
nately, we failed to obtain the crystal of palladacycle intermediate.
Based on our primary study and recent reports,4b,22 we proposed
the mechanism might go through a concerted metalation−
deprotonation (CMD) pathway to give the complex 8 and then
an ArI-coupling pathway for the C−H arylation (Scheme 3).
In conclusion, we have developed an easily accessible and
highly effective directing group for functionalization of C−H
bonds at the δ and ε positions. Arylation of the β-arylethamines
at the ortho position was initially studied and gave good to
excellent yields by using palladium as catalyst under mild
conditions. Detailed mechanistic studies are in progress, and
study of a new application of oxalyl amide as a directing group in
the construction of C−C, C−F, or C−heteroatom bonds is
underway in our laboratory.
Scheme 3. Preliminary Mechanistic Study
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
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Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zbhuang@suda.edu.cn.
*E-mail: yszhao@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) The examples for methoxyl as directing group: (a) Li, G.; Leow,
This research was financially supported by Natural Science
Foundation of Jiangsu Province of China (L210903913), a start-
up fund (Q410901212) from Soochow University, and the
Young National Natural Science Foundation of China
(NO.21402133) for support of this work. The PAPD is also
gratefully acknowledged.
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