Highly regio- And enantioselective synthesis of N-substituted 2-pyridones: Iridium-catalyzed intermolecular asymmetric allylic

Article abstract of DOI:10.1002/anie.201409976

The first iridium-catalyzed intermolecular asymmetric allylic amination reaction with 2-hydroxypyridines has been developed, thus providing a highly efficient synthesis of enantioenriched N-substituted 2-pyridone derivatives from readily available starting materials. This protocol features a good tolerance of functional groups in both the allylic carbonates and 2-hydroxypyridines, thereby delivering multifunctionalized heterocyclic products with up to 98% yield and 99% ee.

Full text of DOI:10.1002/anie.201409976

Angewandte
Chemie
DOI: 10.1002/anie.201409976
Asymmetric Catalysis
Highly Regio- and Enantioselective Synthesis of N-Substituted
-Pyridones: Iridium-Catalyzed Intermolecular Asymmetric Allylic
2
Amination**
Xiao Zhang, Ze-Peng Yang, Lin Huang, and Shu-Li You*
[
3]
Abstract: The first iridium-catalyzed intermolecular asymmet-
ric allylic amination reaction with 2-hydroxypyridines has been
developed, thus providing a highly efficient synthesis of
enantioenriched N-substituted 2-pyridone derivatives from
readily available starting materials. This protocol features
a good tolerance of functional groups in both the allylic
carbonates and 2-hydroxypyridines, thereby delivering multi-
functionalized heterocyclic products with up to 98% yield and
ter. In this regard, the rearrangement reactions starting from
O-substituted pyridines have been developed to address this
3
problem through O to N alkyl migration by sp CÀO bond
[
4]
[5]
cleavage or Claisen rearrangement. Dong et al. disclosed
the first catalytic approach to an efficient O to N alkyl
migration in pyridines in the presence of a ruthenium catalyst
[
4a]
in 2011 (Scheme 1a). Shibata and co-workers reported an
9
9% ee.
N
-substituted 2-pyridones, particularly those possessing
a stereocenter a to the nitrogen atom, have emerged as
important structural motifs in many natural products and
medicinal targets, and they are often crucial for the expression
of interesting biological and pharmacological functions
[
1]
(
Figure 1).
Figure 1. Examples of biologically active chiral 2-pyridones.
Scheme 1. Synthesis of N-substituted pyridones.
Accordingly, a reliable and efficient entry into such a class
of compounds represents a highly important task. However,
a brief survey of the literature reveals that direct approaches
to the preparation of N-alkylated 2-pyridones are much less
well explored, likely because of the competing process
between O and N alkylation given their ambivalent charac-
elegant iridium-catalyzed migration of 2-alkoxypyridines
[
4b]
bearing a secondary O-alkyl group (Scheme 1a). Despite
the progress made in the Claisen rearrangement reactions,
a catalytic asymmetric example for enantioselective synthesis
of pyridones is limited to the report by Batey and co-workers
who describe the palladium(II)-catalyzed [3,3] sigmatropic
[
2]
[
5g,6]
rearrangement of 2-allyloxy pyridines (Scheme 1b).
This
methodology features a wide substrate scope, however, the
reaction of a cinnamyl-alcohol-derived substrate occurs in
a moderate yield (33%) and enantioselectivity (47% ee).
In contrast, dearomatization reactions serve as important
transformations for aromatic compounds, thus giving rise to
[
*] X. Zhang, Z.-P. Yang, L. Huang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
[7]
a variety of ring systems in a very straightforward manner.
Despite the significant progress made with transition-metal-
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin)
[8]
catalyzed allylic dearomatization reactions, only recently
has the strategy been found to be compatible with electron-
[
9]
deficient arenes. The allylic dearomatization reaction of
pyridine was achieved under iridium catalysis in excellent
[
**] We thank the National Basic Research Program of China (973
Program 2015CB856600), NSFC (21025209, 21121062, 21332009)
and the Chinese Academy of Sciences for generous financial
support.
[9a]
yields and enantioselectivity in an intramolecular fashion.
According to the proposed mechanism, the acidic Ha is easily
deprotonated, thus leading to the intermediate which favors
N attack. However, the intermolecular reaction remains
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409976.
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.
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unknown. Inspired by the previous report, we envisaged that
the utilization of 2-hydroxypyridine might allow entry to the
intermolecular asymmetric allylic dearomatization because
there exists a tautomeric equilibrium between 2-hydroxypyr-
a significant increase in yield and enantioselectivity (entry 2)
[
14]
when the Alexakis ligand (S,S,S )-1b was used.
The
a
reaction with 1c also led to a satisfactory result (entry 3).
However, the use of (R,R )-1d or (R )-1e afforded the desired
a
a
[
10]
idine and 2-pyridone.
This methodology will provide
product (4aa) in moderate enantioselectivity but with dis-
appointing yield and regioselectivity (entries 4 and 5). Next,
we turned our attention to examining the effect of the base.
Notably, the reaction did not occur at all in the absence of an
additional base (entry 6, Table 1). Meanwhile, the use of
a direct approach to the asymmetric synthesis of N-substi-
tuted 2-pyridones bearing a stereocenter a to N (Scheme 1c).
Herein, we report our results from this study.
The initial experiment was performed with 2-hydroxypyr-
idine (2a) and cinnamyl methyl carbonate (3a) in the
a weak base such as Et N could only give trace amounts of
3
[
11,12]
presence of a well-developed iridium catalytic system
product (entry 7). In contrast, a stronger organic base such as
including [{Ir(cod)Cl} ] (2 mol%) and the Feringa phosphor-
DBU and various inorganic bases such as tBuOLi, K PO ,
2
3
4
amidite (S,S,S )-1a (4 mol%) in tetrahydrofuran at 508C. By
K CO , and NaH could all be tolerated, thus affording the
2 3
a
using Cs CO as the base, the desired N-alkylation process
desired products in good yields and excellent enantioselec-
tivity (entries 8–12). Among them, Cs CO was found to be
the optimal base (entry 2). Then, varying the amount of
2
3
proceeded in 96% conversion to give the branched product
aa in 84% yield and 94% ee without observation of the O-
2
3
4
alkylation product (entry 1, Table 1). It is likely that the
corresponding h -allyl/Ir intermediate is a soft electrophile,
Cs CO3 indicated that increasing the loading of base to
1 equivalent led to a slightly lower yield. However, 2 equiv-
2
3
which is more easily attacked by the soft 2-pyridone nitrogen
nucleophile rather than the hard oxygen anion of 2-hydrox-
ypyridine. The feasibility of N attack of 2a encouraged us
to investigate other chiral phosphoramidite ligands. To our
delight, the reaction proceeded much more quickly with
alents of Cs CO3 had a detrimental effect on both the
2
conversion and regioselectivity (entries 13 and 14). Above all,
the best conditions were obtained as the following: reaction of
3a with 2 equivalents of 2a in THF with 2 mol% of
[{Ir(cod)Cl} ], 4 mol% of (S,S,S )-1b, and 40 mol% of
[13]
2
a
15]
[
Cs CO at 508C (entry 2, Table 1).
2
3
Under the optimized reaction conditions, the substrate
[
a]
Table 1: Investigation of the reaction conditions.
scope of this intermolecular allylic amination with 2-hydrox-
ypyridines was examined. Firstly, various allylic carbonates
were tested using 2a as the nucleophile. As summarized in
Scheme 2, for the aryl allylic carbonates, substituents on
different positions of the phenyl moiety (4-MeOC H , 4-
6
4
MeC H , 4-FC H , 4-ClC H , 4-BrC H , 3-MeOC H , 3-
6
4
6
4
6
4
6
4
6
4
MeC H , 3-ClC H ) were well tolerated, and their corre-
6
4
6
4
sponding products 4ab–ai were obtained in 80–98% yields
with 98–99% ee. Notably, the generally unfavorable ortho-
substituted substrate was also compatible with this trans-
formation, and 4aj was obtained in 77% yield and 94% ee. To
our delight, heteroaryl allylic carbonates were also suitable
substrates, thus delivering the amination products 4ak and
4al with excellent regioselectivity and ee values, and good
yields upon isolation. In addition to aromatic substituents,
aliphatic allylic carbonates (Me, nPr) were also tested. The
reaction of methyl crotyl carbonate occurred smoothly, thus
affording satisfactory results (4am/5am), but the reaction of
n-propyl-substituted allylic carbonate gave rise to moderate
chemoselectivity and regioselectivity, with excellent enantio-
selectivity (N/O = 86:14; 4an/5an). No notable improvement
on the chemo-, regio-, and enantioselectivity was observed
[
b]
Entry Ligand Base
t [h] Conv. 4aa/5aa
4aa
[
b]
[c]
[d]
[%]
Yield [%] ee [%]
1
2
3
4
5
6
7
8
9
0
1
2
1a
1b
1c
1d
1e
1b
1b
1b
1b
1b
1b
1b
1b
1b
Cs CO3 19
96
95:5
95:5
96:4
48:52
18:82
–
84
94
96
26
6
94
98
93
77
60
–
96
98
99
99
98
99
99
98
2
Cs CO3 1.5 >95
2
Cs CO3 6.5 >95
2
Cs CO3 19
82
26
<5
16
2
Cs CO3 19
2
–
22
22
1.5
–
Et N
–
14
83
79
79
85
87
84
61
3
DBU
tBuOLi 22
K3PO4 1.5
92 >97:3
85
85
94:6
94:6
95:5
94:6
94:6
89:11
[
12g,16]
using [{Ir(dbcot)Cl}2]
(N/O = 82:18; 4an/5an) instead of
1
1
1
1
1
K2CO3 1.5 >95
NaH 1.5 >95
Cs CO3 1.5 >95
[{Ir(cod)Cl} ]. Notably, the bulky t-butyl-substituted allylic
2
[
17]
carbonate was found to be unreactive. Next, the generality
of the reaction with respect to the 2-hydroxypyridine
derivatives using the cinnamyl carbonate 3a as the electro-
philic counterpart was explored. We were pleased to discover
that the reactions of substrates with a range of substituents on
the pyridine moiety, including those bearing either an
electron-donating (5-Me, 4-Me, 3-OH) or electron-withdraw-
ing group (5-Cl, 5-Br, 3-Cl, 3-Br), were highly efficient with
excellent regioselectivity (4/5: 87:13–95:5) and enantioselec-
[
e]
f]
3
2
[
4
Cs CO3 22
2
89
[
a] Reaction conditions: 2 mol% of [{Ir(cod)Cl} ], 4 mol% of 1, 40 mol%
of base, 200 mol% of 2a and 100 mol% of 3a in 2.0 mL THF at 508C.
Unless noted, N/O> 95:5. [b] Determined by H NMR analysis of the
crude reaction mixture. [c] Yield of isolated 4aa. [d] The ee value of 4aa
was determined by HPLC analysis. [e] 100 mol% of Cs CO was used as
the base. [f] 200 mol% of Cs CO was used as the base. cod=1,5-
cyclooctadiene, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, THF=tetra-
2
1
2
3
2
3
hydrofuran.
tivity (4ba–4ha). The reaction of 5-NO pyridone (2i) and 3a
2
2
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Scheme 3. A gram-scale synthesis of 4aa.
Scheme 4. Transformation of the products. dppf=1,1’-bis(diphenyl-
phosphino)ferrocene.
Scheme 5. Conversion of O-allylation products.
PhB(OH) , furnishing 7 (97% ee) without any loss of the
2
[17]
enantiomeric purity (Scheme 4b).
To further shed light on the reaction mechanism, we
synthesized the possible O-alkylated products (8, 9, 10;
Scheme 5). Under the standard reaction conditions, the
reaction did not occur at all with either 2-(cinnamyloxy)pyr-
idine (8) or 2-(but-3-en-2-yloxy)pyridine (9). The reaction
with 2-((1-phenylallyl)oxy)pyridine (10) took a much more
prolonged reaction time (19.5 h) to give the desired
2
8
-pyridone products (4aa and 5aa) in 38% conversion and
0:20 branched to linear selectivity. 4aa was isolated in 28%
yield and 83% ee, which were quite different from the results
obtained from 2a and 3a (branched/linear 95:5; 4aa, 1.5 h,
94%, 98% ee). These data indicate the O allylation followed
by rearrangement or rapid retroreaction of the O-allylation
product is unlikely to be involved.
In conclusion, the first iridium-catalyzed intermolecular
regio- and enantioselective allylic amination reaction with
Scheme 2. Reaction substrate scope. Reaction conditions: 2 mol% of
{Ir(cod)Cl} ], 4 mol% of (S,S,S )-1b, 0.4 mmol of 3, 0.8 mmol of 2,
[
2
a
and 0.16 mmol of Cs CO in 4.0 mL THF at 508C. The ratio of 4/5 and
2
3
1
N/O selectivity were determined by H NMR analysis of the crude
reaction mixture. Catalyst was prepared by nPrNH activation. Unless
[
17]
2
noted, N/O>95:5. [a] Yield of isolated 4. [b] The ee value of 4 was
determined by HPLC analysis. [c] N/O=86:14.
2
-hydroxypyridines has been developed, thus providing
a highly efficient synthesis of enantioenriched N-substituted
2-pyridone derivatives from readily available starting materi-
als. This protocol features a good tolerance of functional
groups in both the allylic carbonates and 2-hydroxypyridines,
thus delivering multifunctionalized heterocyclic products in
excellent yields and enantioselectivity. Further transforma-
tion of the products is ongoing in our laboratory.
was attempted. However, poor reactivity and regioselectivity
[
17]
were observed (4ia: 16%, 87% ee, 4/5: 25:75, 19 h). It is
worth noting that the relatively electron-rich 2-hydroxypyr-
idine derivatives exhibited better regioselectivity than the
electron-deficient ones. The absolute configuration of the
product 4aa was assigned by comparing the sign of the optical
[5g]
rotation with that reported in the literature.
To explore the practicality of the current methodology,
a gram-scale synthesis of 4aa was carried out. The reaction of
a with 3a on a 6.0 mmol scale delivered the desired product
aa in 85% yield and 98% ee (Scheme 3). Then subjecting
aa (98% ee) to a Pt/C-catalyzed hydrogenation reaction
Received: October 11, 2014
Revised: November 9, 2014
Published online: && &&, &&&&
2
4
4
afforded the chiral amide in 94% yield and 98% ee
Scheme 4a). A palladium-catalyzed Suzuki coupling was
conducted with the bromo-containing product 4ha and
(
Keywords: allylic compounds · asymmetric catalysis ·
heterocycles · iridium · synthetic methods
.
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4
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Angewandte
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Communications
Asymmetric Catalysis
X. Zhang, Z.-P. Yang, L. Huang,
S.-L. You*
&&&& — &&&&
Highly Regio- and Enantioselective
Synthesis of N-Substituted 2-Pyridones:
Iridium-Catalyzed Intermolecular
Asymmetric Allylic Amination
Readily available 2-hydroxypyridines are
converted into enantioenriched N-sub-
stituted 2-pyridone derivatives by means
of a highly efficient protocol. The title
reaction features a good tolerance of
functional groups in both the allylic
carbonates and 2-hydroxypyridines, thus
delivering multifunctionalized heterocy-
clic products with up to 98% yield and
99% ee. cod=1,5-cyclooctadiene.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!