Pd(II)-Catalyzed asymmetric oxidative annulation of N-alkoxyheteroaryl amides and 1,3-dienes

Article abstract of DOI:10.1021/acs.orglett.9b00216

The first Pd(II)-catalyzed asymmetric oxidative annulation of N-alkoxyaryl amides and 1,3-dienes is reported, which features particular applicability for quick assembly of different types of chiral heterocycles with high yields and enantioselectivities. A novel chiral pyridine-oxazoline bearing a methoxyl group at the C-5 position and a gem-dimethyl group on the oxazoline moiety was found to be crucial for conversion.

Full text of DOI:10.1021/acs.orglett.9b00216

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd(II)-Catalyzed Asymmetric Oxidative Annulation of
N‑Alkoxyheteroaryl Amides and 1,3-Dienes
Tao Zhang,†,‡,§ Hong-Cheng Shen,†,‡,§ Jia-Cheng Xu,† Tao Fan,† Zhi-Yong Han,*,†
and Liu-Zhu Gong*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: The first Pd(II)-catalyzed asymmetric oxidative
annulation of N-alkoxyaryl amides and 1,3-dienes is reported,
which features particular applicability for quick assembly of
different types of chiral heterocycles with high yields and
enantioselectivities. A novel chiral pyridine-oxazoline bearing a
methoxyl group at the C-5 position and a gem-dimethyl group
on the oxazoline moiety was found to be crucial for
conversion.
ecent years have witnessed a rapid growth in the
Rdevelopment of transition-metal-catalyzed transformations
based on C−H activation processes.1 Although most endeavors
have focused on functionalization, addition, and cross-coupling
reactions, more recently, there has been an increasing number of
reports concerning formal cycloaddition processes.2 These
transformations are extremely appealing as they allow the
formation of two bonds and one ring in a single step, utilizing
abundant and readily available substrates containing C−H
bonds. One successful example is the Pd(II)-catalyzed cascade
C−H activation/allylation reaction, which employs mono-
functionalized arenes and simple 1,3-dienes3,4 as the substrates
(Figure 1a).5 Pioneered by Booker-Milburn and Lloyd-Jones,5a
this strategy has been successfully applied to the formal
annulation reactions of 1,3-dienes with a series of mono-
functionalized arenes, including aryl ureas,5a 2-aryl cyclic-1,3-
dicarbonyls and 1-aryl-2-naphthols,5d benzamides,5b,e arylphos-
phonic acid monoesters,5f and benzoic and acrylic acids.5g
Nevertheless, developing the asymmetric variants has encoun-
tered formidable challenges. Nearly all of the racemic reactions
were carried out under ligand-free conditions, as additional
ligands usually drastically deactivate the catalyst. The major
difficulty is finding appropriate chiral ligands and reaction
conditions to keep the reactivity of the catalyst while meeting the
requirements for the stereocontrol.
So far, the only successful example was developed by our
group using relatively more active aryl urea as the substrate,5h
which could form a palladacycle through C−H activation even at
room temperature in the presence of a cationic Pd(II) catalyst.6
Given the abundance of aryl amides, as well as the need for ideal
methods to synthesize chiral N-heterocycles,7 we sought to
develop a Pd(II)-catalyzed enantioselective annulation of 1,3-
dienes with aryl amides (Figure 1b). Although N-alkoxylbenza-
mides have been frequently investigated in Pd(II)-catalyzed C−
Figure 1. Palladium-catalyzed asymmetric oxidative annulation of N-
alkoxylaryl amides and 1,3-dienes.
H activation processes, related alkenylation and annulation
reactions usually require high temperature (90−110 °C).5b,8
The Pd(II)-catalyzed racemic reaction of 1,3-dienes and N-
methoxybenzamides provides low to moderate yields and only
tolerates 1,3-butadiene-1-carboxylic acid esters.5b As such, the
enantioselective variants require the palladium/chiral ligand
Received: January 17, 2019
© XXXX American Chemical Society
A
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Letter
combination to have not only high activity and stereocontrol
capability but also high stability to avoid the formation of
palladium black at high temperature.9 Herein, we report the
Pd(II)-catalyzed asymmetric oxidative annulation of N-alkox-
yaryl amides and 1,3-dienes using a chiral palladium catalyst
bearing a novel Pyrox-type ligand,10 which properly meets all of
the aforementioned requirements. In addition to high yields,
high enantioselectivities, and the use of a greener oxidant
(O2),11 the current method also features particular applicability
to assemble a variety of different types of chiral heterocycles
efficiently, which are key structural motifs in many bioactive
compounds. As an example, indole-fused heterocycle A is an
adrenergic receptor α1B and α2B antagonist, which may find use
in therapy to reduce blood pressure and promote renal blood
flow.12 Thiophene-fused chiral heterocycle B is a highly potent
PTP1B inhibitor applicable for the treatment of type 2 diabetes
and possibly obesity.13 Similarly, furan-fused compound C is a
potent metalloprotease inhibitor, which is potentially useful for
the treatment of cancers, rheumatic diseases, and atheroscle-
rosis.14
oxygen in methanol at 90 °C, providing the desired product 3a
with only 7% yield (entry 1). Rapid formation of palladium black
was observed during the reaction, indicating severe decom-
position of the palladium catalyst at 90 °C, which might be a
major issue that causes low yield. As such, the addition of a
ligand that could stabilize the palladium catalyst may solve this
problem. Moreover, the chiral ligand should be capable of
promoting the C−H activation process and rendering the
asymmetric allylation process with high stereocontrol at the
same time. Because of our previous success5h in the Pd(II)-
catalyzed asymmetric annulation of aryl ureas and 1,3-dienes
using a chiral sulfoxide-oxazoline ligand,15 ligands L1−L4 were
tested, providing only up to 18% yield and up to 69.5:30.5 er. A
number of chiral pyridine-oxazoline-type ligands, which have
been frequently used in asymmetric Pd(II) catalysis,10,11,16 were
then evaluated for efficacy in the cascade C−H activation/
asymmetric allylation reaction (entries 6−11). The results in
entries 6−8 revealed that a bulky t-butyl group in the ligand is
crucial for the stereocontrol of the reaction. Regarding the
substituents on the pyridine moiety, electron-withdrawing
groups have been reported to render the palladium catalyst
more electrophilic and thus often deliver higher yields and
enantioselectivities. Surprisingly, in this case, an electron-
donating methoxyl group substituent was found superior to
the electron-withdrawing group in terms of both yield and
enantioselectivity (L9 vs L8). In addition, adding a gem-
dimethyl moiety on the oxazoline part17 led to a considerable
boost in both the yield and enantioselectivity (entry 11). A
solvent screen revealed that protonic solvents were beneficial for
the reaction, and methanol turned out to be the optimal one (see
Supporting Information for details). Pd(acac)2 could also
promote the reaction, albeit with slightly lower yield and
enantioselectivity (entry 12 vs entry 11). In the case of
Pd(TFA)2, which has a less basic counteranion, a significantly
decreased yield was obtained with the enantioselectivity
maintained (entry 13). Switching the oxidant to Ag2CO3
resulted in trace product formation (entry 14). Using 2,5-
dimethylbenzoquinone as the oxidant also delivered satisfying
results (entry 15). The reaction conditions using oxygen as the
oxidant was preferred for economic reasons (entry 11).
Our investigation was initiated using 3-indolecarboxylic acid
derived amide 1a and diene 2a as the model substrates (Table
1). As the starting point, the reaction was performed without a
ligand in the presence of Pd(OAc)2 (10 mol %) and 1 atm of
a
Table 1. Optimization of Catalysts and Reaction Conditions
b
c
entry
L
oxidant
yield (%)
er
1
2
3
4
5
6
7
8
9
10
11
12
13
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
Ag2CO3
7
To clarify the ligand effect of the reaction, the reaction
processes were monitored with several representative ligands
(Figure 2).18 The results showed that L9 bearing an electron-
donating group led to a reaction faster thanthat of L8 with a CF3
substituent at the 5-position of the pyridine moiety, and L10
bearing an additional gem-dimethyl moiety rendered the
L1
L2
L3
L4
L5
L6
L7
L8
18
15
9
12
69
70
69
45
75
88 (90 )
74
50
NR
62.5:37.5
0
0
69.5:30.5
72:28
73.5:26.5
90:10
88:12
93.5:6.5
96:4
L9
d
L10
L10
L10
L10
L10
e
93:7
96:4
f
14
15
d
DMBQ
87
96.5:3.5
a
Unless noted otherwise, the reaction of 1a (0.1 mmol) and 2a (0.12
mmol) was carried out with Pd(OAc)2 (0.01 mmol), ligand (0.012
mmol), O2 (1 atm), or oxidant (0.1 mmol) and 3 Å molecular sieves
b
1
(40 mg) in MeOH (1.0 mL) at 90 °C for 24 h. Based on H NMR
analysis of the crude reaction mixture using trimethylbenzene-1,3,5-
tricarboxylate as an internal standard. Determined by HPLC.
Isolated yield. Pd(acac)2 (0.01 mmol) was used instead of
Pd(OAc)2. Pd(TFA)2 (0.01 mmol) was used instead of Pd(OAc)2.
c
d
e
f
Figure 2. Ligand effect on the reaction rate.
B
DOI: 10.1021/acs.orglett.9b00216
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Letter
reaction even faster. The ligand-free reaction almost stopped
after several hours along with the quick formation of palladium
black. A tentative inference on these results is that, at high
temperature (90−110 °C), the decomposition of the palladium
catalyst (facilitated by ligand dissociation) became a severe and
major problem, and electron-rich L9 and L10 that bind tighter
to the palladium metal would be more appropriate. At lower
temperature, where the decomposition of the catalyst is
negligible, electron-poor Pyrox ligands often have better
reactivity.18b,e
to a product with excellent yield and enantioselectivity (3d). For
3-indolecarboxylic-acid-derived amides, either electron-donat-
ing (3e, 3f) or -withdrawing (3g−3i) substituents were well
tolerated. Notably, switching the amide group to the 2-position
of the indole moiety also led to corresponding product with 66%
yield and high enantioselectivity (3j). In addition to indole,
amides derived from other heterocycles, such as benzofuran,
benzothiophene, furan, and thiophene, were all suitable
substrates, providing a variety of chiral heterocyclic products
with 41−93% yields and high enantioselectivities (3k−3o). Due
to lower reactivity, N-alkoxybenzamides were not reactive under
the current reaction conditions. It has been frequently observed
that the presence of acids could facilitate Pd-catalyzed C−H
activation reactions.19 As such, the solvent was changed from
methanol to acetic acid. Gratifyingly, the catalyst system cause
these substrates to undergo the asymmetric cascade reaction,
leading to chiral isoquinolinones in moderate to high
enantioselectivities (3p, 3q). Next, the scope dienes were
investigated for the cascade reaction (3r−3ac). Methyl 1,3-
butadiene-1-carboxylate and its benzyl analogue underwent the
reaction smoothly, providing the corresponding product with
93:7 er (3r, 3s). Various 1-aryl-1,3-butadienes, regardless of the
substitution pattern and the electronic property, were all well
tolerated, affording products 3t−3ab with 51−97% yields and
excellent enantioselectivities. The absolute configurations of 3l
and 3u were determined to be S by X-ray crystallographic
analysis (see the Supporting Information for details). Isoprene, a
readily available bulk chemical, despite its much lower
enantioselectivity, could also undergo the asymmetric cascade
reaction under the standard reaction conditions (3ac).
With this set of conditions in hand (Table 1, entry 11), we
sought to evaluate the substrate scope of the chiral Pd(II)-
catalyzed cascade reaction (Figure 3). The scope of the
To verify the mechanism of the reaction, a same-flask
intermolecular competitive reaction of 1a and [D4]-1a was
performed, and a KIE value of 2.0 was observed, indicating that
the C−H bond cleavage process might be the rate-limiting step
(Scheme 1a). These results and literature precedents all support
Scheme 1. Isotope Labeling Experiment and Derivatization
of the Products
a
Figure 3. Substrate scope. Unless noted otherwise, the reaction of 1
(0.1 mmol) and 2 (0.12 or 0.2 mmol) was carried out with Pd(OAc)2
(0.01 mmol), L10 (0.012 mmol), O2 (1 atm), and 3 Å molecular sieves
(40 mg) in MeOH (1.0 mL) at 90 or 110 °C. bTwo-fold of the diene
was used in MeOH/HOAc (0.8/0.2 mL). cTwo-fold of the diene was
used in HOAc (1 mL).
methodology was first examined in the reactions of 1,3-diene
2a with various heterocyclic arylamides 1 at 90 or 110 °C (3b−
3o). N-Benzyl-substituted and even an unprotected indole
moiety could also be compatible for the reaction (3b, 3c). To
demonstrate the applicability of this method in the synthesis of
fused chiral heterocycles, a gram-scale reaction of 1b and 2a was
performed, leading to 3b with slightly lower yield and
maintained enantioselectivity. In addition to N-OMe amides,
N-OBn amide could also undergo the reaction smoothly, leading
the reaction pathway shown in Figure 1b.5b,8,20 Moreover, to
broaden the synthetic utility of the reaction, the products were
subjected to further transformations. The amide moiety in 3a
could be feasibly reduced to afford O-methylhydroxylamine 4,
which could be further reduced by SmI2 to amine 5. The C−C
double bond of 3a could be readily hydrogenated to afford 6 in
excellent yield. Through a reduction/allylation/ring-closing
C
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cascade sp2 C−H functionalization/intramolecular asymmetric
allylation of N-alkoxyaryl amides and 1,3-dienes using oxygen as
the oxidant and a novel chiral Pyrox as the ligand. The method
also has particular applicability to construct various chiral
heterocycles from simple starting materials efficiently, which
may find wide applications for the synthesis of bioactive
molecules.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00216.
■
S
Experimental details and characterization data (PDF)
Accession Codes
CCDC 1862942 and 1898001 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hanzy2014@ustc.edu.cn.
*E-mail: gonglz@ustc.edu.cn.
ORCID
Zhi-Yong Han: 0000-0002-9225-5064
Liu-Zhu Gong: 0000-0001-6099-827X
Author Contributions
§T.Z. and H.-C.S. contributed equally to this work.
Notes
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Tucker, G.; Bonnet, J.; Sabatini, M. Metalloprotease inhibitors. U.S.
Patent Appl. US5866587A, 1999.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for the financial support from NSFC (Grant
Nos. 21672197 and 21772184) and Chinese Academy of
Science (Grant No. XDB20000000).
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