Organocatalytic Enantioselective 1,6-aza-Michael Addition of Isoxazolin-5-ones to p-Quinone Methides

Article abstract of DOI:10.1002/ejoc.201901907

A thiourea-Br?nsted base bifunctional catalyst allowed the enantioselective 1,6-aza-Michael addition of isoxazolin-5-ones to p-quinone methides to give isoxazolin-5-ones having a chiral diarylmethyl moiety attached to the N atom with fair to good yields and enantiomeric excesses. To the best of our knowledge this reaction represents the first example of enantioselective N-alkylation of isoxazolin-5-ones as well as the first example of enantioselective 1,6-aza-Michael reaction involving p-quinone methides.

Full text of DOI:10.1002/ejoc.201901907

A Journal of
Accepted Article
Title: Organocatalytic enantioselective 1,6-aza-Michael addition of
isoxazolin-5-ones to p-quinone methides
Authors: Ricardo Torán, Carlos Vila, Amparo Sanz-Marco, M. Carmen
Muñoz, José R. Pedro, and Gonzalo Blay
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901907
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901907
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201901907
COMMUNICATION
Organocatalytic enantioselective 1,6-aza-Michael addition of
isoxazolin-5-ones to p-quinone methides
[a]
[a]
[a]
[b]
[a]
Ricardo Torán, Carlos Vila, Amparo Sanz-Marco, M.Carmen Muñoz, José R. Pedro,* and
Gonzalo Blay*[a]
Abstract: A thiourea-Brønsted base bifunctional catalyst allowed the
enantioselective 1,6-aza-Michael addition of isoxazolin-5-ones to p-
biological activity and, therefore, the isoxazol-5-one group has
become a platform for the development of new drug candidates.
Examples include compounds with antibacterial[12] and
cytostatic[ activities as well as enzyme inhibitors for hormone-
quinone methides to give isoxazolin-5-ones having
a chiral
13]
diarylmethyl moiety attached to the N atom with fair to good yields and
enantiomeric excesses. To the best of our knowledge this reaction
represents the first example of enantioselective N-alkylation of
isoxazolin-5-ones as well as the first example of enantioselective 1,6-
aza-Michael reaction involving p-quinone methides.
[
14]
human neutrophil elastase,[15] p38 MAPa
sensitive lipase,
kinase[
16]
and NAD -dependent protein deacetylases (Figure
+
1).[17] Isoxazol-5-ones are also being studied for the development
of new materials for photonic applications.[18] Furthermore,
isoxazol-5-ones are highly functionalized and show a rich
panorama of chemical reactivity, being used in organic synthesis
Asymmetric conjugate addition reactions constitute one of the
most powerful and efficient methods for the enantioselective
construction of C-C and C-X bonds. Excellent levels of regio- (1,4-
vs 1,2- addition) and stereoselectivity have been achieved for 1,4-
as versatile building blocks.[19]
O
O
O
O
N
conjugate additions of a range of nucleophiles and Michael
O
O
acceptors.[
1]
N
RO
HO
O
Compared with the 1,4-addition reaction, the
N
enantioselective 1,6-conjugate addition is more challenging
because of the longer distance between the carbonyl and the
reaction site (reduced reactivity and stereogenic control) as well
as for the presence of an additional electrophilic atom
OH
H N
2
CO
H
OH
O
2
isolated from
isolated from
HNE inhibitor
seeds[10]
Chrysomeline larvae[11] antiinflamatory[15]
legume
O
[
2]
F
(
regioselectivity). Nevertheless excellent results in terms of
= N
R
NMe
cytostatic[13]
O
R = Me
iPr
O
O
regio- and enantioselectivity have been obtained by using metal-
catalysis[3] or organocatalysis.[4] In this context, p-quinone
methides (p-QMs), characterized by a six-membered cyclic bis-
vinylogous enone framework prone to aromatize, have emerged
as reactive electrophiles in enantioselective 1,6-conjugate
additions to give compounds possessing a chiral diarylmethyl
O
N
N
NHAc
R
MAP
p38
kinase inhibitor[16]
antibacterial[12]
N
Figure 1. Examples of natural and bioactive N-substituted isoxazolin-5-ones
[
5]
[5,6]
unit. Most examples involve carbon nucleophiles,
the addition of B (pin) and thioacetic acid have been also
reported.[7] However, there are no examples on enantioselective
although
2
2
Accordingly, the development of new procedures for the
synthesis of this particular heterocyclic and its decoration
constitutes an important goal for organic chemists. Despite this,
the use of isoxazolin-5-ones as nucleophiles in enantioselective
reactions is still underdeveloped. Ma reported the first example
1
,6-conjugate addition of nitrogen nucleophiles to p-QMs, to the
[
8]
best of our knowledge,
although the enantioselective N-
akylation of 2,3-disubstituted indoles with the related aza-p-QMs
has been reported.[9]
On the other hand, the isoxazolin-5-one heterocyclic moiety is
found in a variety of natural products isolated from different plant
families[10] and insects.[11] Many of these compounds show
consisting of a sequential conjugate addition/dearomative
fluorination with nitroolefins catalyzed by a bifunctional chiral
tertiary amino-thiourea catalyst.[20] Later, Wang described the
organocatalytic asymmetric fluorination of 4-substituted
isoxazolinones.[ Peters reported the regioselective C-alkylation
of 4-substituted isoxazolinones forming quaternary stereocenters
by a palladium-catalyzed 1,4-addition to vinyl ketones.[22] The
same group reported later a regioselective asymmetric C-
allylation of isoxazolinones via a iridium-catalyzed N-allylation
followed by a spontaneous aza-Cope rearrangement. In this study,
N-allylated products were obtained when allyl carbonates
substituted with alkyl chains were used.[23] Finally, an
21]
[a]
Mr. Ricardo Torán, Dr. Carlos Vila, Dr. Amparo Sanz- Marco, Prof.
Dr. José R. Pedro and Prof. Dr. Gonzalo Blay
Departament de Química Orgànica
Universitat de València
C/ Dr. Moliner 50, E-46100-Burjassot (València), Spain
E-mail: gonzalo.blay@uv.es (www.uv.es/gblay), jose.r.pedro@uv.es
(
www.uv.es)
[b]
Prof. Dr. M. Carmen Muñoz
Departament de Física Aplicada
Universitat Politècnica de València
E-46071 València, Spain.
organocatalytic
asymmetric
four-component
[5+1+1+1]
cycloaddition via a cascade process that involves a double
alkylation at C4 in isoxazolinones has been developed by Du and
Chen, recently.[24]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901907
COMMUNICATION
In this communication, we report our results on the
asymmetric N-alkylation of isoxazolinones via a 1,6-aza-Michael
addition to p-QMs to give isoxazolinones bearing a chiral
diarylmethyl motif attached to the N atom (Scheme 1). To the best
of our knowledge, this is the first example of asymmetric 1,6-
nucleophilic addition of N-nucleophiles to p-QMs.
alkylated isoxazolinone 3aa (Scheme 1). The best result in terms
of enantioselectivity (66% ee) was obtained with quinine-derived
thiourea
V (Table 1, entry 5). Changing the solvent to
dichloroethane (DCE) allowed to increase the enantiomeric
excess of the reaction product to 85% (Table 1, entry 7). The yield
of the reaction could be improved by adding an excess of p-QM
(
Table 1, entry 8). Finally, using 3 Å MS as an additive permitted
further increase of the enantioselectivity, compound 3aa being
obtained in 65% yield and 87% ee (Table 1, entry 9).
tBu
O
Ph
Me
O
O
tBu
OH
N
catalyst
solvent
O
+
tBu
N
O
Table 2. Enantioselective 1,6-aza-Michael addition of 4(H)-isoxazol-5-ones 1 to
p-quinone methides 2 catalyzed by thiourea V. Reaction scope.[
Me
a]
Ph
2a
tBu
N
1
a
3aa
N
H
H
N
N
CF3
MeO
S
R
1
Ar
N
N
N
tBu
O
CF3
tBu
OH
N N
OH
OH
O
O
N
O
R
2
N
O
N
O
+
tBu
V
(5
mol %)
MeO
MeO
OMe
R1
O
tBu
R2
3Å MS
rt
Ar
N
N
N
N
1
2
DCE,
3
I
II
III
entry
1
R1
R2
2
Ar
t [d]
3
yield [%][b] ee [%][c]
N
Ar
N
N
HN
H
N
H
N
H
H
H
N
N
N
Ar
Ar
1
2
3
4
5
6
7
8
9
1a Me
1b Et
1c Pr
1d Ph
1e cPr
H
H
H
H
H
2a Ph
2a Ph
2a Ph
2a Ph
2a Ph
6
6
6
6
1
1
6
6
6
6
6
6
6
6
6
6
1
1
1
1
2
1
1
3aa
65
51
50
77
78
62
23
66
62
74
43
47
43
20
36
56
75
78
80
76
82
80
71
87
81
81
54
89
47
72
62
88
84
48
89
90
25
81
77
79
88
86
92
82
88
86
MeO
O
MeO
S
MeO
S
O
3ba
3ca
3da
3ea
3fa
N
N
N
IV
V
VI
-
Ar = 3,5 (CF ) C H
3
2
6 3
Scheme 1. Reaction between 3-methyl-4(H)-isoxazol-5-one (1a) and p-QM 2a,
and organocatalysts used in this study.
1f Me Me 2a Ph
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
1a Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2b p-MeC
2c p-MeOC
2d p-ClC
2e p-O NC
2f o-MeOC
2g o-ClC
2h o-BrC
2i m-MeOC
2j m-ClC
2k m-O NC
2c p-MeOC
2d p-ClC
2e p-O NC
2g o-ClC
2i m-MeOC
6
H
4
3ab
3ac
3ad
3ae
3af
Table 1. Enantioselective addition of 3-methyl-4(H)-isoxazol-5-one (1a) to
p-QM 2a. Optimization of the reaction conditions. [
6 4
H
a]
6
H
4
entry
catalyst
solvent
toluene
toluene
toluene
toluene
toluene
toluene
DCE
yield [%][b]
ee [%][c]
56
10
11
12
13
14
15
16
17
18
19
20
21
22
2
6 4
H
1
I
30
36
30
31
48
23
42
48
65
6
H
4
2
II
52
6
H
4
3ag
3ah
3ai
3
III
IV
V
VI
V
V
V
25
6
H
4
4
9
6
H
4
5
66
6
H
4
3aj
6
37
1a Me
1e cPr
2
6
H
4
4
3ak
3ec
3ed
3ee
3eg
3ei
7
85
6
H
8[d]
9[d,e]
DCE
86
1e cPr
1e cPr
6
H
4
DCE
87
2
6 4
H
1e cPr
6 3
H
[
a] 1a (0.1 mmol), 2a (0.1 mmol), catalyst (0.005 mmol), solvent (1 mL), room
temperature, 6 days. [b] Yield after column chromatography. [c] Determined
by HPLC using chiral stationary phases. [d] Reaction carried out with 1a (0.1
mmol) and 2a (0.15 mmol). [e] Reaction carried out in the presence of 3 Å
MS (32 mg).
1e cPr
1e cPr
6 4
H
2j m-ClC
2a Ph
6
H
4
3ej
2 [
3
d]
1e cPr
3ea
The reaction between 3-methy-4(H)-isoxazol-5-one (1a) and
p-QM 2a in toluene at room temperature was used for the
optimization of the reaction conditions (see also SI). Several
organocatalyst (5 mol %) including Cinchona alkaloid bases as
well as bifunctional squaramides and thioureas were screened. In
all the cases the main reaction product obtained was the N-
[
a] 1a (0.1 mmol), 2a (0.15 mmol), V (0.005 mmol), DCE (1 mL), 3 Å MS (32
mg), room temperature. [b] Yield after column chromatography. [c] Determined
by HPLC using chiral stationary phases. [d] Reaction carried out with 1 mmol of
1
e.
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European Journal of Organic Chemistry
10.1002/ejoc.201901907
COMMUNICATION
Under these conditions, we examined next the scope of the
reaction (Table 2).The effect of the substitution on the
isoxazolinone ring was first tested with p-QM 2 (Table 2, entries
In summary, a bifunctional thiourea-Brønsted base catalyst
allowed the first asymmetric 1,6-aza-Michael addition to p-
quinone methides. Isoxazolinones were used as N-nucleophiles
to give isoxazolinones having a chiral diarylmethyl moiety
attached to the N atom. The reaction is broad in scope and
provided the expected products with fair to good yields and high
enantiomeric excesses. Further research to extend this
enantioselective reaction to other nitrogen-containing compounds
is underway in our laboratory.
1-6). Increasing the bulk of the substituent at C3 in the
oxazolinone from methyl to propyl caused a decrease of yield and
enantioselectivity (Table 2, entires 1-3). Isoxazolinone 1d bearing
a phenyl ring at this position also reacted with good yield but
moderate enantioselectivity (Table 2, entry 4). On the other hand,
the presence of a cyclopropyl group attached at C3 increased the
reactivity of the oxazolinone and allowed to obtain the
corresponding product 3ea with good yield (78%) and 89% ee
(
Table 2, entry 5). The disubstituted 3,4-dimethy-4(H)-isoxazol-5-
Experimental Section
onone (1f) also reacted quick but the expected product 3fa was
obtained with only 47% ee (Table 2, entry 6).
General procedure for the 1,6-aza-Michael addition. A round bottom
flask was charged with the para-quinone methide
isoxazolin-5-one 1 (0.1 mmol), 3Å MS (32 mg) and thiourea V (3.7 mg,
.005 mmol). 1,2-Dichloroethane (1 mL) was added and the mixture was
stirred at room temperature until completion (TLC). The MS was removed
by filtration and the resulting solution was chromatographed on silica gel
eluting with hexane:EtOAc mixtures to give compound 3.
2 (0.15 mmol),
Next we examined the scope regarding the p-quinone
methide partner. In general, p-QMs having aryl groups substituted
with electron-donating substituents at either position reacted with
isoxazolinone 1a with lower yields and enantioselectivities than
their analogues having aryl groups substituted with electron-
withdrawing groups (Table 2, entries 7, 8 and 11 vs entries 9, 10,
0
12, 15 and 16). Furthermore, it was found that, for a same
substituent, ortho- or para- substituted rings performed better Acknowledgements
than meta-substituted ones (Table 2, entries 7-10 vs entries 14-
1
6).
Financial support from the Agencia Estatal de Investigación-
Ministerio de Ciencia, Innovación y Universidades (Spanish
Government) and Fondo Europeo de Desarrollo Regional
We also examined the reaction of cyclopropyl-substituted
isoxazolinone 1e with a number of p-QMs (Table 2, entries 17-22).
Again, we found better results in terms of yield and
enantioselectivity compared with the reactions with methyl-
substituted isoxazolinone 1a. In this case, good results were
obtained even for p-QMs having ortho-, meta- or para-substituted
phenyl rings. Finally, it should be noted that the reaction between
isoxazolinone 1e and p-QM 2a was scaled up to 1 mmol scale
with just a minor erosion on the yield and enantioselectivity (Table
(
European Union) (Grant CTQ2017-84900-P) is acknowledged. C.
V. thanks the Spanish Government for a Ramón y Cajal contract
RYC-2016-20187). Access to NMR, MS, and X-ray facilities of
the Servei Central de Suport a la Investigació Experimental
SCSIE-UV) is also acknowledged.
(
(
Keywords: Asymmetric catalysis • enantioselectivity • conjugate
2, entry 23).
addition • heterocycles • alkylation
The configuration of the stereogenic center in compound 3ad
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7
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901907
COMMUNICATION
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compound 3ad. These data can be obtained free of charge from The
[
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901907
COMMUNICATION
Asymmetric organocatalysis
COMMUNICATION
N
Ricardo Torán, Carlos Vila, Amparo
Sanz-Marco, M.Carmen Muñoz, José R.
Pedro,* and Gonzalo Blay*
H
H
N
N
CF
3
R1
Ar
tBu
O
MeO
S
tBu
OH
O
CF
R2
N
O
N
3
O
+
tBu
N
R1
3Å MS
DCE, rt
R2
O
t
Ar
2 examples
Bu
Page No. – Page No.
2
N-regioselective
ee 25-92%
Organocatalytic enantioselective 1,6-
aza-Michael addition of isoxazolin-5-
ones to p-quinone methides
A bifunctional organocatalyst allowed the enantioselective 1,6-aza-Michael addition
of isoxazolin-5-ones to p-quinone methides to give isoxazolin-5-ones having a chiral
diarylmethyl moiety attached to the N atom with fair to good yields and enantiomeric
excesses.
This article is protected by copyright. All rights reserved.