Regioselective catalytic asymmetric C-alkylation of isoxazolinones by a base-free palladacycle-catalyzed direct 1,4-addition

Article abstract of DOI:10.1002/anie.201410933

Isoxazolinones constitute a class of heterocycles utilized for the development of novel drug candidates. The cyclic oxime ester motif is also synthetically useful as it contains functional handles which have previously been used to provide access to an assortment of valuable compound classes not easily accessible by alternative approaches. However, asymmetric methods towards isoxazolinones are notoriously scarce. Herein we report the first catalytic asymmetric alkylations of isoxazolinones forming all-C-substituted quaternary stereocenters. The present studies were driven by the question of how to control the regioselectivity in the competition of different nucleophilic positions. The investigation of a direct 1,4-addition uncovered that a sterically demanding palladacycle catalyst directs the reactivity in the absence of a base nearly exclusively to the nucleophilic C atom, while at the same time it allows for high enantioselectivity and TONs up to 1900.

Full text of DOI:10.1002/anie.201410933

Angewandte
Chemie
DOI: 10.1002/anie.201410933
Asymmetric Catalysis
Regioselective Catalytic Asymmetric C-Alkylation of Isoxazolinones
by a Base-Free Palladacycle-Catalyzed Direct 1,4-Addition
Tina Hellmuth, Wolfgang Frey, and Renꢀ Peters*
Abstract: Isoxazolinones constitute a class of heterocycles
utilized for the development of novel drug candidates. The
cyclic oxime ester motif is also synthetically useful as it contains
functional handles which have previously been used to provide
access to an assortment of valuable compound classes not
easily accessible by alternative approaches. However, asym-
metric methods towards isoxazolinones are notoriously scarce.
Herein we report the first catalytic asymmetric alkylations of
isoxazolinones forming all-C-substituted quaternary stereo-
centers. The present studies were driven by the question of how
to control the regioselectivity in the competition of different
nucleophilic positions. The investigation of a direct 1,4-
addition uncovered that a sterically demanding palladacycle
catalyst directs the reactivity in the absence of a base nearly
exclusively to the nucleophilic C atom, while at the same time it
allows for high enantioselectivity and TONs up to 1900.
Scheme 1. Reported regioselectivity problems in the alkylation of
isoxazolinones 1.[7]
C
yclic five-membered oxime esters, also called isoxazoli-
chiral palladacycle, proceeds with high regio- and enantiose-
lectivity under neutral conditions and remarkably low catalyst
loadings.
nones (systematic name: 4H-isoxazol-5-ones), are broadly
studied owing to their attractive pharmacological proper-
ties.[1] Isoxazolinones 1 are also interesting as valuable
building blocks which permit, for example, a rapid access to
b-amino acids[2] and to various classes of heterocyclic com-
pounds. For instance, they have recently been described as
a practical source for the generation of reactive vinylnitrene
To address the regio- and enantioselectivity issue for this
challenging class of substrates, the addition of isoxazolinone
1a to methylvinylketone (2A, MVK) was investigated as
a model reaction (Table 1).[10] Since we recently found that the
ferrocene bisimidazoline bispalladacycle [FBIP-Cl]2[11,12] is an
efficient and practical precatalyst for asymmetric 1,4-addi-
tions of a-cyanoacetates[13] and azlactones,[14] we initially
focused on this catalyst system.[15,16] In the absence of
a catalyst, reactivity was low and only the N-alkylation
product was detected (entry 1). Since a catalyst loading of
2.5 mol% [FBIP-Cl]2 provided only small amounts of 1,4-
addition product 3aA (entry 2), we utilized the reported
catalyst activation procedure and added silver salts to remove
the otherwise relatively inert chloride ligands.[11b] Activation
by AgOTf resulted in a smooth conversion at room temper-
ature in CH2Cl2. However, the activated catalyst triggered
mainly the N-alkylation and the minor C-alkylation product
was formed in nearly racemic form (entry 3). In contrast,
using anionic ligands with an increased Lewis basicity like
tosylate (entry 4) and heptafluorobutyrate (entry 5) resulted
in a preference for the C-alkylation product, but the
enantioselectivity remained moderate. Interestingly, the
absolute configuration of the major enantiomer depended
on the choice of the anionic ligand with carboxylates favoring
the (R)-antipode (ent)-3aA.
À
intermediates via oxidative addition of the reactive N O
bond to palladium(0) in order to provide bicyclic aziridines or
highly substituted pyrroles.[3–5]
Despite the value of isoxazolinones for pharmaceutical
sciences and organic synthesis, only little is known about the
enantioselective preparation of chiral derivatives by asym-
metric catalysis.[6] In particular, the generation of all-carbon-
substituted stereogenic centers on the ring system by means of
asymmetric catalysis has not yet been accomplished. One
reason seems to be that alkylations of isoxazolinones 1 via the
corresponding enolates 2 (Scheme 1) suffer from low regio-
selectivities due to the competition of nucleophilic C, N, and
O centers, which are prone to alkylation with electrophiles.[7]
Herein, we report a catalytic asymmetric synthesis of
isoxazolinones 3 that is capable of efficiently generating all-
carbon-substituted quaternary stereocenters[8] on the hetero-
cycle. A direct 1,4-addition,[9] which is catalyzed by a planar
[*] Dipl.-Chem. T. Hellmuth, Dr. W. Frey, Prof. Dr. R. Peters
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: rene.peters@oc.uni-stuttgart.de
The same observation was made with the mono-Pd
precatalyst [FIP-Cl]2 activated by different silver salts
(Table 1, entries 6 and 7).[17] In these cases good regioselec-
tivity strongly favoring the C-alkylation product was found,
but the product was still formed with only moderate
Homepage: http://www.peters.oc.uni-stuttgart.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410933.
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Table 1: Optimization of the model reaction.
Table 2: Investigation of the reaction scope.
No.
3
R1
R2
R3
Yield ee
[%][a] [%][b]
1
2
3
4
5
6
7
8
9
3aA Bn
3bA CH2C6H4-4-Me
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
93
93
94
79
71
89
96
96
93
96
86
98
3cA CH2C6H4-4-OMe Ph
3dA CH2C6H4-4-NO2 Ph
3eA CH2C6H4-3-NO2 Ph
3 fA CH2-2-naphthyl Ph
3gA Ph
3hA Me
3iA n-Pr
Ph
Ph
Ph
77[c] 87
89
95
86
83
86
79
85
94
80
96
10 3jA Bn
11 3kA Bn
12 3lA Bn
13 3mA Bn
14 3oD
15 3aB Bn
16 3aC Bn
17 3aD Bn
18 3aE Bn
4-O2N-C6H4 Me
4-MeO-C6H4 Me
3-MeO-C6H4 Me
92[f] 68
No. [Pd]
x mol%
Y
Yield
Yield
ee
Me
(CH2)4
Me
3aA [%][a] 5aA [%][a] 3aA [%][b]
4-MeO-C6H4 88[g] 93
Ph
Ph
Ph
Ph
Et
Ph
92[d] 90
92[e] 91
1
–
–
–
0
5
–
2
3
4
5
6
7
8
9
10
11
12
13
[FBIP-Cl]2 2.5
[FBIP-Cl]2 2.5
[FBIP-Cl]2 2.5
[FBIP-Cl]2 2.5
–
OTf
OTs
20
29
70
6
13
10
37
À27
43
À34
78
80
85
85
95
97
4-MeO-C6H4 96[f] 97
71
26
8
6
2
7
4
5
6
(CH2)2Ph
94[f] 96
O2CCF3 92
OTs 94
O2CCF3 98
OTs 93
O2CCF3 96
OAc
ClO4
ClO4
–
[a] Yield of isolated product 3 (0.5 mmol scale). [b] Enantiomeric excess
of the isolated product determined by HPLC. [c] 0.15 mol% of [PPFIP-Cl]2
was used. [d] 0.2 mol% of [PPFIP-Cl]2 was used. [e] 0.5 mol% of [PPFIP-
Cl]2 was used. [f] 1.0 mol% of [PPFIP-Cl]2 was used.
[FIP-Cl]2
[FIP-Cl]2
2.5
2.5
[PPFIP-Cl]2 2.5
[PPFIP-Cl]2 2.5
[PPFIP-Cl]2 2.5
[PPFIP-Cl]2 2.5
[PPFIP-Cl]2 0.05
[PPFIP-Cl]2 0.05
95
93
95
93
gave pleasing results in terms of reactivity (yield: 71–94%)
and enantioselectivity (ee = 86–98%) using 0.05 mol% of
[PPFIP-Cl]2 at 228C (entries 1–6). An aromatic residue R1
directly connected to the 4-position of the isoxazolinone was
also accommodated under the reaction conditions (entry 7),
but also alkyl groups such as methyl and n-propyl allowed for
high reactivity and useful enantioselectivity with low catalyst
loadings (entries 8 and 9). The residue R2 at the 3-position of
the isoxazolinones could be modified, too. With p-acceptors
(entry 10), p-donors (entry 11), and s-acceptors (entry 12) on
the aromatic moiety the reaction efficiency was always high.
The p-OMe substituent led to a somewhat reduced enantio-
selectivity. Also alkyl residues directly connected to the 3-
position of the isoxazolinones can be employed. While
a substrate with the small methyl group provided the C-
alkylation product 3mA with only moderate enantioselectiv-
ity (entry 13), the bicyclic product 3oD was formed in high
yield and with an ee of 93% (entry 14). Both alkyl and aryl
groups were also well tolerated as residues R3 of the
vinylketone substrates (entries 15–18).
The product constitution and absolute configuration were
determined for compounds 3ma and 3gA by X-ray single-
crystal structure analysis (see the Supporting Information).[20]
The preferred (S)-configuration is in agreement with the
mechanistic proposal shown in Figure 1. We suggest that the
N center of the racemic isoxazolinone 1 coordinates to the
azaphilic catalyst. In C,N-palladacycle complexes neutral
substrates usually strongly prefer to adopt the position trans
to the N donor.[11,12,18] By this coordination of the pronucleo-
5
7
1
[a] Yield determined by H NMR analysis using an internal standard.
[b] Enantiomeric excess determined by HPLC. A minus sign indicates
that the (R)-enantiomer was formed in excess.
enantioselectivity. With a sterically more demanding penta-
phenylferrocene core as in [PPFIP-Cl]2[17,18] it was possible to
significantly improve the enantioselectivity (entry 8). Various
silver salts were again screened for the catalyst activation
using [PPFIP-Cl]2 (entries 8–11).[17,18] It was found that with
this precatalyst always the (S)-enantiomer was formed in
large excess no matter which silver salt was used. As the
conjugate additions usually proceeded with full conversion in
less than 1 h with 2.5 mol% of the precatalyst, much lower
catalyst loadings were investigated and it was found that
a loading of as little as 0.05 mol% still led to very high yields
of the C-alkylation products and even enhanced enantiose-
lectivity (entry 12). Surprisingly, also with the non-activated
catalyst a loading of 0.05 mol% was found to be efficient in
this case (entry 13). This is in contrast to the large majority of
other reactions we have previously reported using this
catalyst type and which require chloride exchange for
a suitable reactivity to facilitate substrate coordination.[17–19]
The optimized reaction conditions were then applied to
different substrates (Table 2). A range of isoxazolinones 1a–f
bearing a benzylic residue R1 with different electron-with-
drawing and -donating substituents in meta or para position
2
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Figure 1. Mechanistic model to explain the stereochemical outcome of
the 1,4-addition. Left: Favored reactive conformation; right: conforma-
tion that is disfavored due to steric and electrostatic repulsion.
Scheme 2. Synthesis of enantiomerically enriched tetrahydro- and hexa-
hydro-4H-pyrano[3,2-d]isoxazoles.
philic substrate enolization is triggered. We suggest that the
plane of the achiral heteroaromatic enol should be almost
coplanar to the square-planar coordination sphere of the PdII
center to minimize repulsion with the sterically demanding
Ph5C5À spectator ligand. Two limiting conformations would be
possible which are both depicted in Figure 1. The one
depicted on the left is in agreement with the observed
absolute configuration. We propose that this is the reactive
conformation, because in the other conformation shown on
the right there are repulsive steric interactions between R2
and the ferrocene core as well as repulsive electrostatic
interactions between a nonbonding orbital of the O(1) atom
and the anionic chloride ligand. Attack of the vinylketone
should occur from the exo direction, since the endo direction
is shielded by the pentaphenylferrocene skeleton. This work-
In conclusion, the present report puts forward the first
examples of enantioselective C-alkylations of isoxazolinones
to form all-carbon-substituted quaternary stereocenters. The
issue of regioselectivity could be addressed by the use of
planar chiral monopalladacycle catalysts. High enantioselec-
tivity was attained by the use of a sterically demanding
pentaphenylferrocene backbone. The readily accessible rac-
emic heterocyclic substrates are expected to undergo an
enolization triggered by the palladacycle in the absence of any
additional reagent. These mild conditions and very low
catalyst loadings attenuate unwanted side reactions and
allow for high atom economy in a direct 1,4-addition to
vinylketones. Since the often necessary activation of pallada-
cycle catalysts by chloride ligand exchange using silver salts is
not required in the present study, the reaction is operationally
remarkably simple to conduct and might thus contribute to
further advance the exploration of isoxazolinones in the
pharmaceutical sciences.
À
ing model can explain 1) the positive effect of the Ph5C5
spectator ligand, 2) decreasing ee values with a smaller
residue R2 like methyl (Table 2, entry 13), and 3) lower ee
values with larger anionic Pd ligands like tosylate (Table 1,
entry 9).
As the products are densely functionalized, further
synthetic manipulations can be envisaged and have already
been described for the racemic 1,4-addition products 3,
including the synthesis of b-amino acids.[2–4,21] To confirm
the synthetic value of the scalemic products 3, we have Experimental Section
General procedure for the catalytic asymmetric Michael addition of
repeated one of the reported sequences for the enantio-
merically enriched compounds 3aA and 3mA to form bicyclic
acetals 7 (Scheme 2).[2] Compounds with the tetrahydro-4H-
pyrano[3,2-d]isoxazole skeleton are of interest for the devel-
opment of new herbicides[22] and may display antibacterial
and antiprotozoal activity,[23] but have (to our knowledge) not
been available so far in enantioenriched form. Compound 7
could be formed in three steps in close analogy to the reported
protocol[2] starting with a regioselective Grignard addition to
the ketone function followed by a regioselective reduction of
the isoxazolinone carbonyl group using LiBH4. Cyclization
with BF3·OEt2 furnished the targeted structures in moderate
yields as a single diastereomer. In addition, we found that
treatment of 3mA with an excess of Grignard reagent directly
generated the bicyclic acetal 8 featuring two adjacent
quaternary stereocenters in a single step with high yield and
isoxazol-5(4H)-ones 1 to vinylketones 2: To the corresponding
isoxazol-5(4H)-one (1, 1 equiv, 0.5 mmol) was added a solution of
[PPFIP-Cl]2 (0.05–1.00 mol%) in CH2Cl2 (3.0 mL) and subsequently
the corresponding vinylketone (2, 2 or 4 equiv, 1.0 or 2.0 mmol). After
the reaction mixture had been stirred for 16 h at room temperature,
the solvent was evaporated and the crude product was subjected to
column chromatography (silica, petroleum ether/ethyl acetate: 4/1).
Received: November 11, 2014
Published online: && &&, &&&&
Keywords: ambidoselectivity · asymmetric catalysis · ferrocene ·
.
palladacycles · quaternary stereocenters
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Communications
Asymmetric Catalysis
Control freak: Enantio- and regioselective
C-alkylations of isoxazolinones to form
products with all-carbon-substituted
quaternary stereocenters are now possi-
ble. The controlled reaction was con-
ducted with a sterically demanding
planar-chiral palladacycle catalyst (TON
up to 1900) in the absence of any other
reagent.
T. Hellmuth, W. Frey,
R. Peters*
&&&& — &&&&
Regioselective Catalytic Asymmetric C-
Alkylation of Isoxazolinones by a Base-
Free Palladacycle-Catalyzed Direct 1,4-
Addition
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!