An Enantioselective Bidentate Auxiliary Directed Palladium-Catalyzed Benzylic C?H Arylation of Amines Using a BINOL Phosphate Ligand

Article abstract of DOI:10.1002/anie.201609337

A new enantioselective palladium(II)-catalyzed benzylic C?H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ-C?H arylations of alkyl amines,

Full text of DOI:10.1002/anie.201609337

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609337
German Edition: DOI: 10.1002/ange.201609337
Synthetic Methods
An Enantioselective Bidentate Auxiliary Directed Palladium-
À
Catalyzed Benzylic C H Arylation of Amines Using a BINOL
Phosphate Ligand
Hao Wang, Hua-Rong Tong, Gang He,* and Gong Chen*
Abstract: A new enantioselective palladium(II)-catalyzed
benzylic CÀH arylation reaction of amines is enabled by the
bidentate picolinamide (PA) directing group. This reaction
provides the first example of enantioselective benzylic g-CÀH
arylations of alkyl amines, and proceeds with up to 97% ee.
The 2,2’-dihydroxy-1,1’-binaphthyl (BINOL) phosphoric acid
ligand, Cs CO , and solvent-free conditions are essential for
2
3
high enantioselectivity. Mechanistic studies suggest that multi-
ple BINOL ligands are involved in the stereodetermining CÀH
palladation step.
O
ver the past decade, palladium-catalyzed auxiliary-
3
directed C(sp )ÀH arylation reactions have been quickly
[1]
developed. However, few generally applicable asymmetric
3
C(sp )ÀH arylation reactions have been reported, and the
realization of this goal will likely require the development of
[
2–8]
new ligand-controlled chemistry.
Most notably, Yu and co-
workers have shown that several palladium(II)-catalyzed
3
monodentate auxiliary directed C(sp )ÀH arylation reactions
can proceed with moderate to excellent enantioselectivity by
the application of chiral amino acids or aminoethyl quinoline
[
3,4]
ligands.
In contrast, despite the diversity of palladium-
3
[9]
catalyzed bidentate auxiliary directed C(sp )ÀH arylations,
Scheme 1. Enantioselective palladium-catalyzed phosphate-mediated
benzylic CÀH arylation directed by N,N-bidentate auxiliary groups.
they present a more challenging platform for enantioselective
transformations because of the single available coordination
site on the palladium catalyst during the stereodetermining
[3d]
CÀH palladation step. Overall, ligands capable of modu-
benzylic b-CÀH arylation of 3-arylpropanamides with aryl
lating palladium-catalyzed bidentate auxiliary directed C-
iodides can be made enantioselective with a BINOL-based
3
[8]
(
sp )ÀH functionalization reactions are still very scarce, let
phosphoric amide (L1) and acid (L2) as ligands. Herein, we
alone chiral ligands. We have previously observed that
BnO) PO H uniquely enhances palladium-catalyzed picoli-
report a complementary palladium(II)-catalyzed PA-directed
(
enantioselective benzylic g-CÀH arylation of 3-arylpropyl-
2
2
3
[4]
namide (PA) and aminoquinoline (AQ) directed C(sp )ÀH
amines using the BINOL phosphoric acid L2. The observa-
[10,11]
alkylation reactions with alkyl halides (Scheme 1).
More
tion of a nonlinear ligand effect suggests that multiple BINOL
recently, Duan and co-workers reported that the AQ-directed
phosphate ligands are involved in the stereodetermining CÀH
palladation step.
Although we originally suspected that (BnO) PO H
2
2
[
*] H. Wang, H.-R. Tong, Prof. Dr. G. He, Prof. Dr. G. Chen
State Key Laboratory and Institute of
Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin)
Nankai University, Tianjin 300071 (China)
E-mail: hegang@nankai.edu.cn
activates alkyl halides by acting as a phase-transfer catalyst
[11a,b]
for silver salts,
subsequent studies have demonstrated
that simple organic phosphates can influence other types of
palladium-catalyzed bidentate auxiliary directed CÀH func-
[11c–e,12–14]
tionalization reactions with or without silver.
Duanꢀs
gongchen@nankai.edu.cn
report showed that either BINOL phosphoric amide or acid
Prof. Dr. G. Chen
Department of Chemistry
The Pennsylvania State University
University Park, Pennsylvania 16802 (USA)
E-mail: guc11@psu.edu
can act as a chiral ligand, thus rendering the CÀH palladation
[8]
step enantioselective. Encouraged by Duanꢀs findings, we
sought to study the effect of BINOL ligands on the PA-
3
[4]
directed g-C(sp )ÀH arylation of amines. Initially, we
observed poor yields from the g-CÀH arylation of unsubsti-
tuted 3-phenylpropylamine under various conditions. How-
ever, the PA-derivatized 1,1-dimethyl-3-phenylpropylamine
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201609337.
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[15]
1, a more conformationally constrained substrate, provided
(20 mol%) gave a noticeably decreased ee value (entry 17),
2
a in excellent yield, but with poor ee value under Duanꢀs
while a lower loading of palladium (5 mol%) gave a slightly
improved ee value (entry 15). Finally, a 97% yield of isolated
2a with 91% ee was obtained when 5 mol % [PdCl2-
(MeCN) ], 2.5 equivalents of Cs CO , and 25 mol% of L2
conditions (Table 1, entry 1). Use of L2 gave a slightly higher
ee value (entry 4), and the choice of solvent had a significant
impact on yield and ee value (entries 3–5). Similar to Duanꢀs
system, modification of the BINOL scaffold resulted in
decreased ee values (entries 6–9). Higher reaction concentra-
tion gave increased ee values (entry 4 versus 10). 2a was
obtained in 88% yield and 62% ee when the reaction was
performed without solvent (entry 12). Lowering the reaction
temperature to 1108C and adding an additional equivalent of
Cs CO further improved enantioselectivity (entries 13 and
2
2
3
were used at 1108C without solvent. It is also worth noting
that 1) use of Cs CO is critical for obtaining high ee values
2
3
(entries 20–22); 2) Pd(OAc)2 provides
a slightly lower
ee value (entry 25); and 3) a decreased loading of palladium
(2 mol%) gave a slightly lower yield but similar ee value
(entry 19).
We then subjected 1 to a PA-directed CÀH arylation with
2
3
1
4). Interestingly, a higher loading of the palladium catalyst
a variety of aryl iodides under these reaction conditions
(Scheme 2). Aryl iodides bearing functional
groups such as bromide (2d) and ester (2 f) were
well tolerated. The electronics of the aryl iodide
influence the ee value of the reaction. Electron-
rich aryl iodides gave relatively higher ee values
3
Table 1: Enantioselective g-C(sp )ÀH arylation of 1 with 4-iodotoluene.
(2j versus 2k). The product 2e from 4-iodoanisole
was obtained with an excellent ee value of 97%
[
16]
(
er: 98.4/1.6). The steric characteristics of the
aryl iodide also have a significant impact on the
ee value of the reaction. In general, meta-substi-
tuted aryl iodides gave lower ee values than para-
substituted aryl iodides (2e versus 2i). The ortho-
substituted aryl iodides, such as 2-iodoanisole,
showed little reactivity (< 5% yield).
To evaluate the reaction with other amine
substrates, we prepared a series of PA-derivatized
1
,1-dimethyl-3-arylpropylamines (4) by palladium-
3
(
II)-catalyzed g-C(sp )ÀH arylation of 1,1-dime-
thylpropylamine (3) with various aryl iodides
Eq. (1); DMA = N,N’-dimethylacetamide]. The
[
a]
[b]
Entry Pd, base (equiv), T
L (equiv) Solvent
Yield [%] ee [%]
[
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
Pd1 (0.1), Cs CO (1.5), 1408C L1 (0.2) p-xylene 90
30
32
19
42
35
14
16
<3
<3
50
<3
62
76
79
88
91
62
79
91
81
35
<3
86
89
84
82
2
3
Pd1 (0.1), Cs CO (1.5), 1408C L1 (0.2) tAmOH 98
products 4 were obtained in good to excellent
yields and excellent monoselectivity under the
optimized reaction conditions [1.5 equiv of CuF2,
DMA solvent, 1008C; see the Supporting Infor-
mation].
2
3
Pd1 (0.1), Cs CO (1.5), 1408C L2 (0.2) p-xylene 78
2
2
3
3
Pd1 (0.1), Cs
CO
(1.5), 1408C L2 (0.2) tAmOH 87
66
Pd1 (0.1), Cs CO (1.5), 1408C L3 (0.2) tAmOH 82
Pd1 (0.1), Cs CO (1.5), 1408C L2 (0.2) MeCN
2
3
2
3
Pd1 (0.1), Cs CO (1.5), 1408C L4 (0.2) tAmOH 74
2
3
As shown in Scheme 3, 4, bearing different 3-
Pd1 (0.1), Cs CO (1.5), 1408C L5 (0.2) tAmOH 57
2
3
3
aryl substituents underwent PA-directed g-C(sp )À
Pd1 (0.1), Cs CO (1.5), 1408C L6 (0.2) tAmOH 52
2
3
[
c]
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
Pd1 (0.1), Cs CO (1.5), 1408C L2 (0.2) tAmOH 90
H arylation reactions in moderate to excellent
ee values under the standard reaction conditions.
Sterically bulky aryl substituents on the amine
substrate significantly diminish the ee value of the
reaction (5 f versus 2e). The directing ability of
various analogues of picolinic acid was also
evaluated (Scheme 4). Interestingly, all modifica-
tions of the pyridine ring led to a decrease in
enantioselectivity and/or yield. Notably, substitu-
tion at the C6 position of pyridine (6e and 6g)
caused dramatic loss in reactivity.
2
3
Pd1 (0.1), K CO (1.5), 1408C
L2 (0.2) tAmOH
9
88
93
99
99
99 (97)
99
99
87
90
47
5
2
3
Pd1 (0.1), Cs CO (1.5), 1408C L2 (0.2) neat
2
3
Pd1 (0.1), Cs CO (1.5), 1108C L2 (0.2) neat
2
3
Pd1 (0.1), Cs CO (2.5), 1108C L2 (0.2) neat
2
3
Pd1 (0.05), Cs CO (2.5), 1108C L2 (0.2) neat
2
3
[d]
Pd1 (0.05), Cs CO (2.5), 1108C L2 (0.25) neat
2
3
Pd1 (0.2), Cs CO (2.5), 1108C L2 (0.2) neat
2
3
Pd1 (0.05), Cs CO (2.5), 1108C L2 (0.05) neat
2
3
Pd1 (0.02), Cs CO (2.5), 1108C L2 (0.25) neat
2
3
Pd1 (0.05), Rb CO (2.5), 1108C L2 (0.25) neat
2
3
Pd1 (0.05), K CO (2.5), 1108C L2 (0.25) neat
2
3
Pd1 (0.05), Na CO (2.5), 1108C L2 (0.25) neat
2
3
Palladium-catalyzed PA-directed CÀH aryla-
Pd2 (0.05), Cs CO (2.5), 1108C L2 (0.25) neat
88
99
99
88
2
3
tion reactions likely proceed through a catalytic
cycle featuring CÀH palladation, oxidative addi-
tion of ArI, and CÀC bond-forming reductive
Pd3 (0.05), Cs CO (2.5), 1108C L2 (0.25) neat
2
3
Pd4 (0.05), Cs CO (2.5), 1108C L2 (0.25) neat
2
3
Pd1 (0.05), Cs CO (2.5), 1108C L1 (0.25) neat
2
3
[
10b,17]
elimination.
Following the mechanistic model
[
[
a] Yields are based on HPLC analysis of reaction mixture on a 0.2 mmol scale.
b] Determined by HPLC using a chiral column. [c] Used 0.5 mL of solvent here
compared to 1 mL of solvent used for other entries. [d] Yield of isolated products.
See Supporting Information for additional screening conditions.
proposed for the BINOL phosphoric amide L1
3
mediated b-C(sp )ÀH arylation of AQ-coupled
[8]
alkyl carboxylic acid, we initially thought that
2
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Scheme 4. Evaluation of the directing ability of PA analogues.
iodotoluene under otherwise standard reaction conditions, we
did not observe a linear effect on the ee value of 2a
[
21]
(
Scheme 5a). Furthermore, the yield of 2a was influenced
by the ee value of L2. These observations indicate that more
than one L2 molecule is involved in the enantioselective CÀH
3
Scheme 2. Substrate for the g-C(sp )ÀH arylation of 1. Yields are of
palladation step. As shown in Scheme 5b, the identity of the
products isolated from a 0.2 mmol scale reaction.
alkali cation also strongly influences the yield and ee value of
+
2
e, thus suggesting the involvement of Cs in the L2-mediated
CÀH palladation step. Because of its large size and high
+
coordination number, Cs tends to form high-valent coordi-
[
22]
nation complexes, and even clusters.
We suspect that
a monomeric 1:1 Cs(1)–L2(1) complex might dimerize to
+
form cluster Cs(2)–L2(2), from which a Cs can dissociate to
À
[23]
give Cs(1)–L2(2) (Scheme 5c). To explain the nonlinear
+
ligand effect and the critical role of Cs , we hypothesize that
either Cs(1)–L2(2) or Cs(2)–L2(2) may act as the ligand
À
a single L2 ligand was responsible for the enantioselective g-
CÀH palladation of the PA-derivatized alkyl amines by
controlling the enantioselective CÀH palladation step (see
[
18]
a concerted metalation deprotonation (CMD) mechanism
model B). Unlike the monomeric L2 ligand in model A, one
[
19,20]
II
(
see model A in Scheme 5d).
However, when the
L2 of the Cs complex binds to Pd while the other one serves
enantiopurity of L2 was varied in the reaction of 1 and 4-
as an internal base (Scheme 5d). However, the involvement
of other forms of a Cs–L2 cluster and/or carbonate species
cannot be ruled out, and CÀH palladation facilitated by
monomeric-L2 may still provide a competing pathway.
In summary, we report an enantioselective palladium(II)-
catalyzed bidentate auxiliary directed benzylic CÀH arylation
reaction of PA-derivatized alkyl amines with aryl iodides.
Complementary to the previously reported BINOL phospho-
ric amide mediated enantioselective CÀH arylation of amino-
quinoline-derivatized alkyl carboxylic acid substrates, this
reaction provides the first example of enantioselective g-CÀH
arylation of PA-derivatized alkyl amines with up to 97% ee.
The combination of a BINOL phosphate ligand and Cs CO
2
3
base under solvent-free conditions is essential to achieve high
enantioselectivity. Mechanistic studies suggest that a cesium–
phosphate complex might be involved in the stereodetermin-
ing CÀH palladation step. Additional mechanistic investiga-
tions and the development of new chiral phosphate ligands
are currently under investigation to broaden the scope of the
enantioselective palladium-catalyzed bidentate auxiliary
directed CÀH functionalization.
3
Scheme 3. g-C(sp )
ÀH arylation of 4. Yield is that of product isolated
from a 0.2 mmol scale reaction run under the standard conditions.
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Acknowledgments
We thank the State Key Laboratory of Elemento-Organic
Chemistry at Nankai University for financial support of this
work.
[
[
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Keywords: arylations · CÀH activation · enantioselectivity ·
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Angewandte
Communications
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[
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Received: September 23, 2016
Ma, W. Hu, Angew. Chem. Int. Ed. 2013, 52, 13356 – 13360;
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Synthetic Methods
H. Wang, H.-R. Tong, G. He,*
G. Chen*
&&&& — &&&&
An Enantioselective Bidentate Auxiliary
Directed Palladium-Catalyzed Benzylic
CÀH Arylation of Amines Using a BINOL
Seeking direction: A new enantioselective
palladium(II)-catalyzed benzylic CÀH
tions are essential for high enantioselec-
tivity. Mechanistic studies indicate that
multiple BINOL ligands are involved in
the stereodetermining CÀH palladation
Phosphate Ligand
arylation of amines is enabled by the
bidentate picolinamide (PA) directing
group. The BINOL phosphoric acid
ligand, Cs CO , and solvent-free condi-
step.
2
3
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!