Catalytic Asymmetric Chlorination of Isoxazolinones
Nick Wannenmacher,[a] Noah Keim,[a] Wolfgang Frey,[a] and René Peters*[a]

Organic compounds featuring a chlorine substituted stereo-
center are frequently found in nature and are interesting for
pharmaceutical applications and as synthetic building blocks.
Catalytic methods to generate such stereocenters by C,H bond
functionalization are still relatively rare. Here we report the first
catalytic asymmetric chlorination of isoxazolinones, a syntheti-
cally and biologically interesting class of heterocycles, which
can be considered as precursors for β-aminoacids. The title

reaction was catalyzed with high enantioselectivity by a planar
chiral ferrocene based palladacycle in high to excellent yields. It
is showcased that the products are valuable for post-synthetic
transformations. An SN2 reaction proceeded with smooth
inversion of the absolute configuration. The substitution
product could then be transformed into an α-azido β-aminoacid
derivative via a reductive, diastereoselective ring opening.

Introduction

Chlorine substituted stereocenters are found in a large number
of natural products and pharmaceutically interesting
compounds.[1] Thousands of natural products containing a
chlorine or bromine atom bound at a stereocenter are known.[1]

A prominent example is the cytotoxic polyhalogenated mono-
terpene halomon isolated from the red algae Portieria
hornemannii.[2] It is one of only few substances showing activity
against all 60 tumor cell lines of the National Cancer Institute.[3]

Enantiopure alkylchlorides are also valuable synthetic sub-
strates for SN2 type reactions. Even tertiary alkylchlorides were
used for the construction of C� F, C� O, C� S, C� N, and C� C
bonds at tetrasubstituted stereocenters, concomitant with an
inversion of the absolute configuration.[4] Nevertheless, exam-
ples for SN2 type reactions with such tertiary alkylchlorides are
rare due to steric blocking of the reactive C� Cl bond.[4]

As a result of the utility of alkylchlorides, the construction of
C� Cl bonds is an important strategy in organic synthesis and
pharmaceutical industry.[4b] Nevertheless, the number of cata-
lytic asymmetric methods forming Cl-substituted quaternary
stereocenters is still quite limited. Next to desymmetrizations of
prochiral alkylchlorides[5] and halofunctionalization of alkenes[6]

there are mainly α-chlorinations of carbonyl derivatives.[ 4b]

Substrates like enolizable β-ketoesters and oxindoles capable of
two-point binding to a catalyst to create rigid reactive
intermediates have been primarily reported.[4,7] In addition,
asymmetric chlorinations of aldehydes were accomplished by

enamine catalysis,[8] ketenes were chlorinated by Lewis base[9]

and silyl enolethers by Lewis acid catalysis.[10]

In 2016, Wang et al. reported the catalytic asymmetric
chlorination of pyrazolones, a biologically interesting class of
heterocycles, using a cinchona alkaloid as Brønsted base
catalyst at low reaction temperatures.[11] They also demon-
strated the synthetic utility of the chlorination products in SN2
reactions.

In contrast, for the structurally related isoxazolinones
(systemic name: isoxazol-5-(4H)-ones)[12] catalytic asymmetric
chlorinations have not been reported. These cyclic 5-membered
oxime esters are also biologically interesting heterocycles[13]

which, in addition, can be regarded as versatile β-aminoacid
precursors.[14] Enantioselective chlorination of the isoxazoli-
nones’ 4-position might thus create new possibilities for the
synthesis of enantiopure pharmacologically interesting β-ami-
noacid derivatives.[15]

Herein, we report the first catalytic asymmetric chlorination
of isoxazolinones. It was achieved by a planar chiral palladacycle
catalyst, which we recently also reported for the fluorination of
this class of heterocycles.[14] In addition, an example is shown
for the application in an SN2 reaction and the post-synthetic
transformation into a β-aminoacid derivative.

Results and Discussion

Substrate 1 a was used for the development of the title reaction
(Table 1) on a 0.1 mmol scale. The investigation was started by
surveying the impact of different chlorination agents A–E using
the chloride bridged planar chiral ferrocenyl palladacycle
[PPFIP� Cl]2

[16] (PPFIP: 1’,2’,3’,4’,5’-pentaphenylferrocenyl imidazo-
line palladacycle) as precatalyst (entries 1–5). In previous work
we found that ferrocene based imidazoline palladacycle cata-
lysts are capable of efficiently activating pronucleophiles
featuring C,N-π-bonds in α-position to a C,H-acidic C atom,
such as isoxazolinones,[17,14] in asymmetric catalysis with high
compatibility of functional groups.[18]

[PPFIP� Cl]2 C1 (2.5 mol%) was activated with AgOTs
(5 mol%) by a chloride/tosylate exchange in the presence of

[a] N. Wannenmacher, N. Keim, Dr. W. Frey, Prof. Dr. R. Peters
Institut für Organische Chemie
Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart, Germany
E-mail: rene.peters@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202200030

© 2022 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.

www.eurjoc.org

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http://orcid.org/0000-0002-6668-4017
https://doi.org/10.1002/ejoc.202200030


MeCN prior to use. By that monomeric catalyst species are
formed which should facilitate substrate binding.[16] Performing
the reactions for 17 h at room temperature in chlorobenzene,
moderate yields and low enantioselectivity were attained
employing N-chlorosaccharin C and N-chlorobenzenesulfonei-
mide D as chlorination agents (Table 1, entries 3 & 4). In
contrast, quantitative product yields were obtained for reagents
N-chlorosuccinimide A (entry 1), N-chlorophthalimide B (en-
try 2) and 1,3-dichloro-5,5-dimethyl-hydantoin E (entry 5). The
best enantioselectivity of 66% ee was noted with B. To increase
enantioselectivity, the effect of lower reaction temperatures
was studied. At 0 °C, the ee could be improved to 83% (entry 6),
but a further temperature decrease resulted in lower ee’s
(entry 7). Acetic acid was then examined as additive, which
might support the formation of an enol intermediate. By this
change, the enantioselectivity was enhanced to 86% ee
(entry 8). Different silver salts AgX were probed for catalyst
activation, but both more (Lewis) basic anionic ligands X- such
as acetate (entry 9) and acetylacetonate (entry 10), but also less
basic ones such as triflate (entry 11) did not provide any
improvements. With the non-activated catalyst, racemic product
was obtained (entry 12). No reaction occurred in the absence of
a catalyst under these conditions. This suggests that [PPFIP� Cl]2
is still acting as Lewis acidic catalyst, but not capable of

controlling a face-selective attack of B at the assumed enol
intermediate (see below).

Finally different solvents were applied. Among them
toluene (entry 14) was found to be slightly more suitable than
chlorobenzene, but the best solvent of those tested was
dichloromethane. Under the conditions of entry 13, 2 a was
formed in quantitative yield with an enantiomeric excess of
96% in a nearly quantitative yield. Under the same conditions,
with the Lewis basic solvents THF (entry 15) and acetonitrile
(entry 16) inferior results were obtained.

[PPFIP� Cl]2 was also compared to other ferrocene based
palladacycles from our portfolio (Table 2). The beneficial effect
of the 1’,2’,3’,4’,5’-pentaphenylcyclopentadienide ligand is appa-
rent from the results obtained with [FIP� Cl]2 (entry 2),[16a,d,h]

where the product was still formed in high yield, but with only
moderate enantiomeric excess. Moreover, there is a positive
influence of the imidazoline moiety in [PPFIP� Cl]2 compared to
the oxazoline moiety in [PPFOP� Cl]2.

[16d] Poor results in terms of
yield and enantioselectivity were obtained with the bispallada-
cycle precatalyst [FBIP� Cl]2 (entry 4).

[19]

For [PPFIP� Cl]2 it was found that quantitative yields are still
possible with lower catalyst loadings, yet at the expense of a
reduced enantioselectivity (entries 5 and 6). For the investiga-
tion of the scope of substrates, 2.5 mol% of [PPFIP� Cl]2 was
thus used (Table 3). The impact of several other residues R2 than

Table 1. Development of the title reaction.

# ‘Cl+ ’ X T
[°C]

Solvent HOAc
[equiv.]

Yield
[%][a]

ee
[%][b]

1 A OTs 22 PhCl – 99 44
2 B OTs 22 PhCl – 99 66
3 C OTs 22 PhCl – 47 26
4 D OTs 22 PhCl – 60 34
5 E OTs 22 PhCl – 99 10
6 B OTs 0 PhCl – 99 83
7 B OTs � 10 PhCl – 99 36
8 B OTs 0 PhCl + 99 86
9 B OAc 0 PhCl + 69 0
10 B acac 0 PhCl + 70 0
11 B OTf 0 PhCl + 99 71
12 B – 0 PhCl + 69 0
13 B OTs 0 CH2Cl2 + 99 96
14 B OTs 0 toluene + 99 88
15 B OTs 0 THF + 10 75
16 B OTs 0 MeCN + 67 12

[a] Determined by 1H-NMR of the crude product using mesitylene as internal standard. [b] Determined by HPLC.

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benzyl (entry 1) was studied. With a 2-naphthylmethyl group
the highest ee was attained (97%, entry 2). In addition, the
effect of several functionalized benzyl moieties was examined.
para-Substituents on the aryl rings were all well tolerated for
electron donors and acceptors (entries 3–6). ortho-Substitution

also allowed for an excellent yield, but the ee was decreased
(entry 7).

Next to the benzylic residues, products with alkyl groups R2

were formed in high yields and with high enantioselectivity
(entries 8 & 9). With an allyl residue the ee was decreased to
73%, while the product yield was still high (entry 10). In
addition to these substrates with aliphatic groups R2, the
method can be applied to those bearing aromatic groups
directly bound to the enolizable C atom, as is exemplified in
entry 11. Also in this case, yield and enantioselectivity were
high.

Moreover, it was found that variations of the aromatic
residues R1 at the imino C atom are possible (entries 12–14).
However, as a limitation we found that substrates with a simple
alkyl group R1 such as methyl permitted only poor enantiose-
lectivity, whereas the product yields were still good (not
shown).

The absolute configuration of 2 a could be determined as
(R) by X-ray single crystal structure analysis (Figure 1),[20] which
is in agreement with the configurational outcome for further
functionalizations of this substrate class catalyzed by a PPFIP
catalyst.

We assume that the reaction mechanism is very similar to
those previously suggested for our 1,4 additions and fluorina-
tions of isoxazolinones, applying the same type of
catalyst.[14,17,21] It should involve coordination of the substrate by
its N-atom to the azaphilic Pd(II) center thus triggering
substrate enolization, that might be facilitated by HOAc. Due to
the acidic conditions we think that the formation of an enolate
intermediate is unlikely in this method.[22] The stereochemical
outcome might be explained by our previously reported
working models.[14,17]

To showcase the synthetic value of the reaction products,
we studied the option of an SN2 displacement. Prior to use, the
chlorination product 2 a was crystallized in order to get almost
enantiopure material. In analogy to the work by Wang using
pyrazolones,[11] use of NaN3 in dry DMSO delivered the
substitution product in high yield and with a negligible level of
racemization (98% ee). The x-ray crystal structure analysis of
3[20] confirms an SN2 mechanism, because an inversion of the
stereochemical configuration was determined (see box in
Scheme 1).

A reductive ring opening of the isoxazolinone ring was
achieved under the conditions which we recently reported for
fluorinated isoxazolinones. Under substrate control a diastereo-
meric ratio of 4 :1 was found. Oxidation of the primary alcohol

Table 2. Catalyst Investigation.

# Precatalyst X Yield
[%][a]

ee
[%][b]

1 [PPFIP� Cl]2 2.5 99 96
2 [FIP� Cl]2 2.5 92 54
3 [PPFOP� Cl]2 2.5 95 34
4[c] [FBIP� Cl]2 2.5 41 33
5 [PPFIP� Cl]2 2.0 99 86
6 [PPFIP� Cl]2 1.5 99 83

[a] Determined by 1H-NMR of the crude product using mesitylene as
internal standard. [b] Determined by HPLC. [c] 10 mol% of AgOTs was
used for catalyst activation.

Table 3. Investigation of the Substrate Scope.

# 1/2 R1 R2 Yield
[%][a]

ee
[%][b]

1 a Ph Bn 98 96
2 b Ph 2-naphthyl� CH2 96 97
3 c Ph 4-Br� C6H4� CH2 86 91
4 d Ph 4-NC� C6H4� CH2 93 92
5 e Ph 4-OMe� C6H4� CH2 85 90
6 f Ph 4-Me� C6H4� CH2 88 88
7 g Ph 2-Cl� C6H4� CH2 96 77
8 h Ph Me 88 94
9 i Ph n-Pr 92 95
10 j Ph Allyl 93 73
11 k Ph Ph 82 89
12 l 4-Cl� C6H4 Bn 95 95
13 m 4-MeO� C6H4 Bn 86 87
14 n 4-Cl� C6H4 Me 90 89

[a] Yield of isolated product. [b] Determined by HPLC.

Figure 1. X-ray crystal structure analysis of 2 a.

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function followed by esterification gave the α-azido β-amino-
acid derivative 6 as synthetically interesting building block. In
addition, substitution product 3 was further employed for a
copper catalyzed azide/alkyne cycloaddition to form 1,2,3-
triazole 4.

Conclusion

In conclusion, we have reported the first catalytic asymmetric
chlorination of isoxazolinones. This was enabled by a planar
chiral palladacycle catalyst derived from a 1’,2’,3’,4’,5’-pentaphe-
nylferrocenyl imidazoline ligand. The products were formed
with high enantiomeric excess and in good to excellent yields.
One chlorination product was exemplarily used for a nucleo-
philic substitution reaction with NaN3, which proceeded with
almost complete inversion of the absolute configuration, thus
pointing to an SN2 type reaction of the tertiary chloride. An
interesting α-azido β-aminoacid derivative could be prepared
by a diastereoselective ring opening reaction. These studies
further emphasize the value of isoxazolinones for asymmetric
synthesis.

Experimental Section
General procedure for the asymmetric chlorination of isoxazoli-
nones: A solution of the corresponding isoxazolinone 1 (1.0 equiv.),
catalyst ([PPFIP� Cl]2 (2.5 mol%) activated by AgOTs (5 mol%)), N-
chlorophthalimide B (1.1 equiv.) and HOAc (1.0 equiv.) in chloro-
benzene (0.2 M) was stirred at 0 °C for 17 h. The solution was then
directly subjected to column chromatography (PE/EE, 20 :1) to
isolate the product.

Acknowledgements

We thank the analytical service of the Institute of Organic
Chemistry at the University of Stuttgart. Moreover, we are grateful
to Lennart Schumacher for his experimental and general
laboratory support. Open Access funding enabled and organized
by Projekt DEAL.

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in
the supplementary material of this article.

Keywords: Aminoacids · Asymmetric catalysis · Ferrocene ·
Nucleophilic substitution · Palladacycles

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Scheme 1. Post-synthetic transformations of 2 a, including the synthesis of
an α-azido β-aminoacid derivative 6, and an X-ray crystal structure analysis
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[20] Deposition Numbers CCDC 2133764 (2 a) and 2133787 (3) contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe Access Structures
service www.ccdc.cam.ac.uk/structures.

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[22] Review on Pd(II)-enolates in asymmetric catalysis: a) Y. Hamashima, M.
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Manuscript received: January 12, 2022
Revised manuscript received: February 10, 2022
Accepted manuscript online: February 14, 2022

Research Article
doi.org/10.1002/ejoc.202200030

Eur. J. Org. Chem. 2022, e202200030 (5 of 5) © 2022 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH

Wiley VCH Montag, 28.02.2022

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