Enantioselective Aza-Friedel-Crafts Reaction of Heteroarenes with in situ Generated Isoxazolium Ions via Chiral Phosphoric Acid Catalysis

Article abstract of DOI:10.1002/adsc.202100408

An asymmetric organocatalytic aza-Friedel-Crafts reaction was developed to give the enantioenriched Δ⁴-isoxazoline scaffold bearing a quaternary-substituted stereogenic centre in good-to-excellent yields and enantioselectivity (50–99%, 55–>99% ee). This protocol involves the in situ generated isoxazolium ions in the presence of a chiral phosphoric acid followed by the heteroarene addition through asymmetric counteranion-directed catalysis. (Figure presented.).

Full text of DOI:10.1002/adsc.202100408

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doi.org/10.1002/adsc.202100408
Enantioselective Aza-Friedel-Crafts Reaction of Heteroarenes
with in situ Generated Isoxazolium Ions via Chiral Phosphoric
Acid Catalysis
You-Song Cheng,a Shih-Hsien Chan,a Gunda Ananda Rao,a
Ramani Gurubrahamam,b,* and Kwunmin Chena,*
a
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan R.O.C.
E-mail: kchen@ntnu.edu.tw
Department of Chemistry, Indian Institute of Technology Jammu, Jagti, NH 44, Jammu (J&K), 181221, India
b
E-mail: guru.ramani@iitjammu.ac.in
Manuscript received: April 1, 2021; Revised manuscript received: June 13, 2021;
Version of record online: June 26, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100408
the developments have been witnessed on in situ
Abstract: An asymmetric organocatalytic aza-Frie-
generation of iminium species and their transformation
del-Crafts reaction was developed to give the
into chiral entities.[6] In this context, aza-Friedel-Crafts
enantioenriched Δ4-isoxazoline scaffold bearing a
alkylation (aza-FCA) reactions with heteroarenes were
quaternary-substituted stereogenic centre in good-
well studied through chiral phosphoric acid (CPA)
to-excellent yields and enantioselectivity (50–99%,
catalysis.[7–10] Particularly, the strategies involving
cyclic ketimines are highly attractive as these could
55–>99% ee). This protocol involves the in situ
generated isoxazolium ions in the presence of a
render target-orientated heterocyclic scaffolds containg
chiral phosphoric acid followed by the heteroarene
a quaternary stereogenic centre.[11]
addition through asymmetric counteranion-directed
catalysis.
Among the five-membered heterocyclic com-
pounds, isoxazoline is an important scaffold that is
found in various biologically active molecules and
natural products.[12] Although significant advances
Keywords: organocatalysis; aza-Friedel-Crafts reac-
have been made in the field of asymmetric catalysis,
tion; 2,3-dihydroisoxazole; ion-pair catalysis; chiral
only a few protocols for the asymmetric synthesis of 3-
phosphoric acid
or 4-isoxazoline skeleton have been reported thus
far.[13] In general, optically enriched 4-isoxazolines can
be accessed via the transitional-metal-catalysed 5-
Asymmetric organocatalysis has demonstrated to be an endo-dig cyclization of either isolated or in situ
elegant approach to generate various cationic aromatic generated chiral propargylic N-hydroxylamines.[14] In
systems, enabling their reactions with suitable addition, this skeleton can be constructed by the
nucleophiles.[1] For example, functionalisation of asymmetric [3+2]-cycloaddition of nitrones and al-
pyrylium,[2] isobenzopyrylium,[3] pyridinium,[4] and kynes
using
(iso)quinolinium[5] systems through asymmetric coun- catalysis.[15]
teranion-directed catalysis (ACDC) or anion-binding Sun, Alemán, Fraile, and their co-workers have
chiral
ligand/transitional
metal
catalysis has been reported (Figure 1). In recent years, independently developed a metal-free organocatalytic
strategy to construct the intriguing moiety (Sche-
me 1a–1b).[16] Zhang and co-workers constructed this
skeleton during their investigations on the reactivity of
enynones with N-hydroxylamines via a bifunctional
catalysis (Scheme 1c).[17] Recently, the transitional
metal-catalysed asymmetric hydrogenation of isoxazo-
lium salts has been reported to afford chiral 4-isoxazo-
lines with moderate-to-good enantioselectivity.[18] This
Figure 1. Asymmetric functionalization of various aromatic
cationic species.
is a useful strategy to obtain the desired motifs by a
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Table 1. Optimization of the reaction.
Entry[a] CPA
1
2/3 Solvent
t
4 %[b]
ee[c]
1
2
3
4
5
6
7
I
1a 2a DCM
1a 2a DCM
1a 2a DCM
1a 2a DCM
1a 2a DCM
1a 2a DCM
1a 2a toluene
1a 2a toluene
1a 2a o-xylene 2.5 d
1a 2a m-xylene 5.0 d
1b 2a m-xylene 5.0 d
1c 2a m-xylene 5.0 d
1d 2a m-xylene 5.0 d
1e 2a m-xylene 5.0 d
1a 3a m-xylene 5.5 d
20 min 4a(92) À 14
50 min 4a(87) À 18
20 min 4a(99) À 18
II
III
IV
V
VI
V
V
V
V
V
V
V
V
V
V
4.5 h
3.5 h
2 h
4a(97) À 26
4a(97) 42
4a(81) À 12
4a(99) 48
4a(93) 62
4a(83) 60
4a(74) 69
4b(66) 69
4c(69) 59
4d(74) 51
4e(53) 70
4f(31) 93
4f(79) 92
Scheme 1. Organocatalytic enantioselective synthesis of 4-iso-
xazolines.
3 h
2 d
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
16
simple reduction reaction. However, the prerequisite
synthesis of stable isoxazolium salts and metal-
catalysed hydrogenolysis limited the versatility of the
protocol. All previously reported strategies deliver
isoxazolines containing an asymmetric methine carbon
atom.[14–18] The development of synthetic protocols to
construct quaternary centres remains elusive.[19] To the
best of our knowledge, the development of a protocol
to deliver 4-isoxazolines containing a quaternary-
substituted stereogenic centre has not yet reported.
Herein, we envisaged the in-situ generation of iso-
xazolium ions followed by aza-FCA reaction with
heteroarenes under CPA catalysis (Scheme 1d).
1a 3a toluene
1.0 d
[a] All reactions were carried out with 1 (0.1 mmol, 1.0 eq.), 2a/
3a (0.11 mmol, 1.1 eq.), and organocatalyst (3 mol%) in
°
given solvent (0.2 M) at 0 C, unless mentioned.
[b] NMR yield.
[c] Determined from chiral HPLC.
[d]
°
Reaction was carried out at À 20 C.
The starting racemic 2,3-dihydroisoxazole deriva-
tives 1 were prepared readily from the addition of N- increase in the enantioselectivity was observed when a
hydroxylamine derivatives to 2-oxo-3-butynoates.[20] pyrrole (3a) was screened; however, a lower yield of
Toward this end, the reaction was attempted by using 4f was noticed (Table 1, entry 15, 31% yield, 93% ee).
1a and indole 2a in the presence of a CPA catalysis. The chemical yield was substantially improved when
°
In all the acid studied, the desired product 4 was the reaction was carried out at 0 C in toluene (Table 1,
obtained in high to quantitative yield in dichloro- entry 16, 79% yield and 92% ee). The reaction
methane (Table 1, entries 1–6). The use of (S)-TRIP completed in one day and the enantioselectivity
(CPA-V) catalyst afforded the target product with remains high. It is noteworthy to mention that we also
moderate enantioselectivity (Table 1, entry 5, 97% observed the formation of a probable side product
yield, 42% ee). Next, we attempted to optimise the (isoxazole) in variable amounts where the desired
reaction conditions by varying the solvent and temper- product yield was not quantitative.[20,21]
ature. Slightly improvement in enantioselectivity was
With the optimised reaction conditions in hand, the
observed (up to 69% ee) when non-polar solvents and substrate scope was explored by using a variety of 2,3-
at lower temperature were used (Table 1, entries 7–10). dihydroisoxazoles, pyrroles, and indole derivatives.
°
When the reaction was performed at À 20 C, the target The chemical results were compatible with different
4-isoxazoline was obtained in high yield that required substituent on the ester moiety in the 2,3-dihydroisox-
a prolonged reaction time. Modification of the ester azoles, and the corresponding pyrrole-substituted 4-
substituent in the 2,3-dihydroisoxazole derivatives 1 isoxazoles 4g–4h were isolated in good yields and
(1b–1e) failed to improve the enantioselectivity enantioselectivity (Scheme 2, up to 83% yield, 93–
(Table 1, entries 11–14). To our surprise, a significant 95% ee). The optimised reaction conditions tolerate the
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tional organocatalyst.[8g,i–j,9a,11c–e] It was also observed
that N-alkylated heteroarenes are superior coupling
partners than that of NÀ H free heteroarenes in CPA
catalysed aza-FCA reaction.[8c–d] Interestingly, the
demonstrated protocol is also compatible to N-alky-
lated indoles as we observed the respective product 4y
with N-methylindole in persistent chemical and optical
yields (67% yield and 75% ee). This could indicate no
significant role of indole NÀ H group in the demon-
strated ACDC reaction.
The synthetic utility of the 4-isoxazoline skeleton is
high; it can be used to prepare valuable 1,3-amino
alcohols, β-lactams, oxazolidine, pyrrolidine heterocy-
clics, and acyl aziridines.[23] The stereochemistry of 4j
was tentatively assigned through X-ray crystallography
and the other products were assigned accordingly.[24]
The ORETP diagram of 4j is shown in Figure 2.
A plausible mechanism for this organocatalytic
reaction was proposed based on experimental results
(Scheme 3).[25] The initial protonation of the hydroxyl
group in the racemic 4-isoxazoline by CPA-V catalyst
gave species A. This was followed by the dehydration
process that resulted in the isoxazolium ion B
stabilised by a chiral phosphate anion. The asymmetric
Scheme 2. Substrate scope.
electronic properties (electron-withdrawing or elec- counteranion directs the addition of the pyrrole to the
tron-donating effect) and position of the substituent electrophile that leads to the formation of ion-paired
(ortho-, meta- or para-) on the aryl in the 2,3-
dihydroisoxazole when pyrrole was used. The corre-
sponding pyrrole-substituted products 4i–4o were
obtained in good-to-high chemical yields and enantio-
selectivity (62–91% yield and 88–>99% ee). In
addition, a reaction with pyrrole and a heteroaryl
bearing 2,3-dihydroisoxazole was carried out. Interest-
ingly, we isolated enantioenriched isoxazoline 4p
containing 2-thienyl and 2-pyrrole in good yield (74%
yield, 86% ee). The reaction was found to be tolerant
to N-Boc protecting group on the isoxazoline skeleton
as 4q was isolated in good yield and enantioselectivity
Figure 2. ORTEP of 4j (50% ellipsoid probability).
(61% yield, 75% ee). However, the use of 2-methyl
pyrrole afforded the corresponding 4r with reasonable
yield and enantioselectivity (50% yield, 55% ee). As
anticipated, 3-methyl pyrrole afforded a regio-isomeric
mixture consisting of 2,4-disubstituted pyrrole 4sa as
the major product (64% yield) and 2,3-disubstituted
pyrrole 4sb as the minor product (18% yield) with
satisfactory enantioselectivity (89 and 90% ee, respec-
tively). A series of indole-substituted isoxazoline
derivatives were obtained (4t–4x) with slight decrease
of stereoselectivities (64-72% ee) with reasonable to
high chemical yields (62–99% yield). The reactivity
increased when the electron-donating substituents were
present in the indole substrate (4w–4x).
It is well investigated the crucial role of NÀ H group
in CPA catalysed asymmetric FCA reaction.[22] A clear
detrimental rate and enantioselectivity was observed
with N-alkylated heteroarenes which indicates the
strong coordination of the NÀ H group with the bifunc-
Scheme 3. Plausible mechanism for the organocatalytic reac-
tion.
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Experimental Section
Procedure for enantioselective synthesis of 4f: A solution of
substituted pyrrole 3a (0.11 mmol, 1.1 equiv.) in toluene was
added to a stirred solution of hydroxy 4-isoxazoline derivative
1a (0.1 mmol, 1.0 equiv.) and CPA catalyst (S)-TRIP-V
°
(3 mol%, 2.3 mg) in toluene at 0 C. The reaction mixture was
stirred at the same temperature for 24 h and the reaction mixture
was quenched with saturated NH4Cl solution. The contents
were brought to ambient temperature slowly and extracted with
dichloromethane (2×10 mL). The combined organic extracts
were washed with deionized water, dried on anhydrous MgSO4,
filtered, and evaporated to afford the residue. The crude product
was purified by using flash column chromatography on silica
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This study was supported by the Ministry of Science and
Technology of Taiwan (MOST 108-2113-M-003-012). RG
thankful to Indian Institute of Technology Jammu for providing
a seed grant (SGT-100035).
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