Pd-Catalyzed regio- And enantioselective allylic substitution with 2-pyridones

Article abstract of DOI:10.1039/c9cc07482a

An efficient method for the asymmetric synthesis of N-substituted 2-pyridones via Pd-catalyzed regio- and enantioselective allylic substitution of hydroxyl-containing allylic carbonates with 2-pyridones has been developed. By using a palladium complex in situ generated from Pd₂(dba)₃·CHCl₃ and phosphoramidite L2 as a ligand, the process allowed rapid access to N-substituted 2-pyridones with complete chemo- and regioselectivities and good to high enantioselectivities.

Full text of DOI:10.1039/c9cc07482a

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Pd-Catalyzed regio- and enantioselective allylic
substitution with 2-pyridones†
Cite this: Chem. Commun., 2019,
55, 13168
Sardaraz Khan,
Babar Hussain Shah, Ijaz Khan, Meiqi Li and Yong Jian Zhang
*
Received 24th September 2019,
Accepted 7th October 2019
DOI: 10.1039/c9cc07482a
rsc.li/chemcomm
An efficient method for the asymmetric synthesis of N-substituted enantioselectivities (Scheme 1a). Therefore, the development of
2-pyridones via Pd-catalyzed regio- and enantioselective allylic new asymmetric catalytic methods for the construction of chiral
substitution of hydroxyl-containing allylic carbonates with N-substituted 2-pyridones from readily accessible starting materials
2-pyridones has been developed. By using a palladium complex is highly appealing.
in situ generated from Pd2(dba)3ÁCHCl3 and phosphoramidite L2
The Pd-catalyzed asymmetric allylic substitution is one of
as a ligand, the process allowed rapid access to N-substituted the most powerful methods for carbon–carbon and carbon–
2-pyridones with complete chemo- and regioselectivities and good heteroatom bond formation.4 However, for unsymmetric mono-
to high enantioselectivities.
substituted allylic substrates, Pd-catalyzed allylic substitution
generally gave linear products.5 Even so, several approaches have
Chiral N-substituted 2-pyridones are prevalent motifs in a been achieved in the Pd-catalyzed branch-selective allylic sub-
variety of important medicinally relevant agents and biologically stitution with high enantioselectivities by ligand control.6 Since
active natural products, such as rhinovirus 3C-protease inhibitors Trost and co-workers reported the Pd-catalyzed regio- and
(Fig. 1).1 Although several synthetic protocols from chiral amines enantioselective allylic alkylation of vinylepoxide with phthalimide,7
are available,2 the catalytic asymmetric approaches to directly the branch-selective control by hydrogen-bond interactions between
access this skeleton are largely underdeveloped.3 Only a few nucleophiles and allylpalladium intermediates has been exploited.8
examples of asymmetric catalytic methods have been documented Most recently, our group reported the Pd-catalyzed asymmetric
to date. In 2010, Batey and co-workers reported a Pd(II)-catalyzed decarboxylative allylic cycloaddition of vinylethylene carbonates
asymmetric [3,3] sigmatropic rearrangement of 2-allyloxy pyridines (VECs) with unsaturated electrophiles to afford versatile oxo-
to afford N-substituted 2-pyridones with high enantioselectivities.3a heterocycles with complete branch-selectivities.9 The branch-
Breit3b,c and You3d reported recently the Rh- and Ir-catalyzed selective control has also been achieved by the cooperative
asymmetric allylic substitution of 2-pyridones respectively to catalysts of the palladium and boron reagent.10 Based on our
furnish N-substituted 2-pyridones in high chemo-, regio- and continuous efforts for the development of Pd-catalyzed branch-
and enantioselective allylic substitution, we are interested in
allylic substitution with 2-pyridones to construct enantioenriched
Fig. 1 Examples of rhinovirus 3C-protease inhibitors with a 2-pyridone
ring.
School of Chemistry and Chemical Engineering, and Shanghai Key Laboratory of
Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China. E-mail: yjian@sjtu.edu.cn
† Electronic supplementary information (ESI) available: Detailed experimental
procedures; characterization data of all of the new compounds; copies of HPLC
chromatographs, and 1H and 13C NMR spectra of the products. See DOI: 10.1039/
Scheme 1 Chemo-, regio- and enantioselective allylic substitution with
2-pyridones.
c9cc07482a
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N-substituted 2-pyridones. To the best of our knowledge, there is no To our delight, the reaction proceeded smoothly in the presence
report on Pd-catalyzed branch-selective allylic substitution with of a catalyst generated in situ from the Pd2(dba)3ÁCHCl3 and
2-pyridones. Based on our previous research results, we envisioned Feringa’s phosphoramidite11 L1 as a ligand in THF at 20 1C to
that a zwitterionic allylpalladium intermediate A could be obtained afford the desired product 3a in 88% yield with complete chemo-
by the reaction of the palladium catalyst with VEC (Scheme 1b). The and branch-selectivities, albeit a low enantioselectivity was
branch-selective control would be possible by the hydrogen-bond observed (entry 1). We next found that the enantioselectivity could
interactions between the proton of 2-hydroxypyridine and oxygen be increased with the decrease of the reaction temperature
anion of intermediate A to produce the desired branch-substituted (entries 2–4). Thus, the enantioselectivity could be improved to
allylic product. Herein, we report the successful execution of 63% when the reaction was conducted at À40 1C (entry 4).
these ideas and present H-bond directed Pd-catalyzed regio- and However, further improvement in the enantioselectivity was not
enantioselective allylic substitution with 2-pyridones, a practical observed upon reacting with other phosphoramidite ligands12
and efficient approach which allows rapid access to N-substituted (entries 5–9), even though high yields could be obtained in some
2-pyridones with complete chemo- and regioselectivities and good cases (entries 5–7). Next, we examined the allylic substitution of
to high enantioselectivities.
(Z)-hydroxyl-containing allylic carbonate 1b using palladium
Based on our previous studies,9 the initial investigations catalysts bearing different phosphoramidites in THF at À40 1C
focused on the examination of the allylic substitution of H-VEC 1a (entries 10–15). Surprisingly, the reactions of allylic carbonate 1b
and hydroxypyridine (2a) as standard reaction partners using a gave very different results in comparison with that of H-VEC 1a.
palladium catalyst bearing phosphoramidite as a ligand (Table 1). Thus, the reactions with phosphoramidites derived from Binol
proceeded smoothly to afford the allylic product 3a in high yields
with complete chemo- and regioselectivities (entries 10–12), and
Table 1 Condition optimizationa
the reaction with ligand L2 showed the best enantioselectivity
(95 : 5 er, entry 11). The reactions were not effective when BINAP
or a Trost ligand was used (entries 16 and 17). The reaction
efficiency was remarkably decreased when the reactions were
conducted with corresponding allylic acetate 1c and benzoylate
1d (entries 18 and 19). Although the reaction of vinylepoxide 1f
with 2a proceeded smoothly under the identical conditions with
entry 11, poor enantioselectivity was observed (entry 21). The
allylic substitution of (E)-allylic carbonate 1e gave almost the same
results with that of (Z)-isomer 1b (entries 20 versus 11). We finally
examined the reaction of allylic carbonate 1b with 2a in the
different solvents (see ESI†). However, the enantioselectivity could
not further improve. Notably, when the reaction of 1b with 2a was
performed in MeOH, a 3.7 : 1 branch/linear ratio was observed.
These results implied that the hydrogen-bond interaction between
2-hydroxypyridine and the allylpalladium intermediate played an
important role for the regioseletive control. Although the allylic
donors 1a, 1b, 1e and 1f should give the same allylpalladium
intermediate A as described in Scheme 1, these results indicated
that the reaction efficiency was highly affected in the leaving
group of the allylic donors.4
With optimal conditions (Table 1, entry 11) in hand, the reaction
scope of the protocol was evaluated by the allylic substitution of
allylic carbonate 1b with various substituted 2-pyridones. As shown
in Table 2, a variety of substituted 2-pyridones bearing different
electronic and steric properties was tolerated under the reaction
conditions to afford the corresponding allylic pyridones 3 in high
yields (81–91%) with complete chemo- and regioselectivities and
acceptably high enantioselectivities (89 : 11 to 96 : 4 er). A wide range
of functional groups, such as halogen, protected amine, nitro-,
cyanide, aldehyde, and ester groups, could be successfully installed
with a high efficiency. Notably, the compounds 3e and 3f would be
useful intermediates for the synthesis of medicinally interesting
rhinovirus 3C-protease inhibitors.1d
T
(1C)
Yieldb
(%)
Entry
1
Ligand
erc (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1c
1d
1e
1f
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L2
L3
L4
L5
L6
20
0
88
83
52
57
91
81
93
62
28
81
87
89
70 : 30
75.5 : 24.5
80.5 : 19.5
81.5 : 18.5
59 : 41
48 : 52
60.5 : 39.5
60 : 40
38 : 62
75.5 : 24.5
95 : 5
21 : 79
69.5 : 30.5
—
—
—
31 : 69
80 : 20
76 : 24
94.5 : 5.5
57.5 : 42.5
À20
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
9
10
11
12
13
14
15
16
17
18
19
20
21
31
Trace
Trace
Trace
26
42
30
BINAP
Trost
L2
L2
L2
92
82
L2
a
Reaction conditions: Pd2(dba)3ÁCHCl3 (2.5 mol%), ligand (10 mol%),
1 (0.2 mmol), 2a (0.2 mmol), solvent (2.0 mL), 36 h. b Isolated yields.
c
Determined by HPLC using a chiral stationary phase. The absolute
configuration was assigned by comparing the sign of the optical
We next turned our attention toward the examination of the
Pd-catalyzed allylic substitution of longer hydroxyl-containing
rotation with that reported.3a
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Table 2 Pd-Catalyzed allylic substitution of 1b with various substituted 2
pyridones 2 a
at 40 1C. The reaction of methoxyl allylic carbonate 1i showed a
poor branch selectivity (b : l = 1 : 1.5) to afford the branch-
product 4c in 39% yield with a low enantioselectivity (28% ee).
These results implied that the hydrogen-bond interaction between
2-hydroxypyridines and the allylpalladium intermediate as revealed
in Scheme 1 played an important role not only for the regio-
selectivity control, but also for the reactivity. The allylpalladium
intermediates generated from hydroxymethyl and hydroxyethyl
allylic carbonates could build an effective hydrogen-bond inter-
action with 2-hydroxypyridines, thus the corresponding allylic
products could be given in high yields with high levels of
regioselectivities.
The reaction conditions were also tolerated for the allylic
substitution of 1b with 4-hydroxypyridine 5 to afford the
N-alkylated product 6 in 40% yield with 83.5 : 16.5 er, but low
regioselectivity was observed (b : l = 1 : 1.4, Scheme 3).13
To gain more information on the reaction pathway, we
conducted the reaction of the possible O-alkylated product 7
under the standard reaction conditions (Scheme 4). The reaction
proceeded smoothly to give N-alkylated product 3a in 73% isolated
yields with 63% ee and 5 : 1 branched to linear selectivity, which
were quite different to the results obtained from the reaction of 1b
with 2a. These results indicated that the O-alkylation followed by
the rearrangement or rapid retroreaction of the O-alkylated product
is unlikely to be involved.3b,d
The utility of the present process was demonstrated by
the product derivatization (Scheme 5). Dihydropyran 9a and
tetrahydrooxepine 9b could be obtained in high yields by the
a
Reaction conditions: Pd2(dba)3ÁCHCl3 (2.5 mol%), L2 (10 mol%), 1b
(0.2 mmol), 2 (0.2 mmol), THF (2.0 mL), 36 h. The yields are of isolated
materials. The enantiomeric excesses were determined by HPLC using a
chiral stationary phase.
allylic carbonates with 2-pyridone 2a. As revealed in Scheme 2,
the allylic substitution of hydroxylethyl allylic carbonate 1g
also proceeded smoothly to afford the product 4a in 76%
yield with 95 : 5 er, albeit the branch-selectivity was slightly
decreased (b : l = 13 : 1). However, the allylic substitution of
hydroxylpropyl allylic carbonate 1h did not work at all under
the reaction conditions, even when the reaction was carried out
Scheme 3 Pd-Catalyzed allylic substitution of allylic carbonate 1b with
4-pyridone 5.
Scheme 4 Conversion of the O-allylated product 7 to the N-allylated
product 3a.
Scheme 2 Pd-Catalyzed allylic substitution of allylic carbonates 1g–1i
with 2-pyridone 2a.
Scheme 5 The elaboration of 3a and 4a.
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In conclusion, we have developed an efficient method for
the asymmetric synthesis of N-substituted 2-pyridones via a
Pd-catalyzed regio- and enantioselective allylic substitution
of hydroxyl-containing allylic carbonates with 2-pyridones. By
using a palladium complex in situ generated from Pd2(dba)3Á
CHCl3 and phosphoramidite L2 as a ligand, the process allowed
rapid access to N-substituted 2-pyridones with complete
chemo- and regioselectivities and good to high enantioselec-
tivities. The reaction pathway has been rationalized by the
control experiments, and the synthetic utility was demonstrated
by the product derivatization. Further studies on extending the
scope of the hydrogen-bond directed regioselective allylic substi-
tution with other nucleophiles are currently underway, and will be
reported in due course.
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This work was supported by the National Natural Science
Foundation of China (21572130, 21871179), and Shanghai Jiao
Tong University. We thank the Instrumental Analysis Center of
Shanghai Jiao Tong University for HRMS analysis.
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A. W. Kleij, J. Am. Chem. Soc., 2016, 138, 14197; ( f ) S. Soriano,
There are no conflicts to declare.
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