Access to Isoxazolidines through Visible-Light-Induced Difunctionalization of Alkenes

Article abstract of DOI:10.1021/acscatal.9b03567

An access to isoxazolidines featuring visible-light induced aerobic difunctionalization of alkenes is reported. α-Amino radicals generated via oxidative decarboxylation of N-aryl glycines are added to alkenes and the resulting radical intermediates are tr

Full text of DOI:10.1021/acscatal.9b03567

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Letter
Access to Isoxazolidines through Visible-
Light Induced Difunctionalization of Alkenes
Hui Yang, Guo Wei, and Zhiyong Jiang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03567 • Publication Date (Web): 23 Sep 2019
Downloaded from pubs.acs.org on September 23, 2019
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Access to Isoxazolidines through Visible-Light
Induced Difunctionalization of Alkenes
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Hui Yang,§Guo Wei,*,† and Zhiyong Jiang*,†,‡
†Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan, People’s Republic of China 475004
‡School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, People’s Republic of China 453007
§College of Pharmacy, Henan University, Jinming Campus, Kaifeng, Henan, People’s Republic of China 475004
ABSTRACT: An access to isoxazolidines featuring visible-light induced aerobic
difunctionalization of alkenes is reported. α-Amino radicals generated via oxidative
decarboxylation of N-aryl glycines add to alkenes and the resulting radical intermediates
are trapped by superoxide. The peroxides undergo swift intramolecular amine oxidation
to provide the valuable isoxazolidines. Alkenes with varied functionalization can be
applied. The isoxazolidine ring can be readily opened via reduction by zinc in acetic acid
to afford γ-lactams in high yield.
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KEYWORDS: Photoredox Catalysis, Aerobic, Alkene difunctionalization, Isoxazolidines,
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Glycines
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The isoxazolidines, owing to their application as important intermediates for the synthesis
of a variety of natural products and their unique pharmaceutical bioactivities (Figure 1),
are the focus of increasing research interests in recent years.1 Though 1,3-dipolar
cycloaddition (1,3-DC), among other available approaches for the synthesis of
isoxazolidines, is the most straightforward and conventional approach, preparation of
nitrones frequently requires demanding conditions.2 Cyclizations of unsaturated
hydroxyamines via electrophilic, radical, metal catalysis or Michael addition mechanism
represent the recent advances in this field (Scheme 1a).3
H
H
N
O
N
H
O
OH
H
H
N
O
N
O
H
N
N
O
O
HN
N
8
NH2
H
O
O
COMe
N
HN
H
OH
O
N
N
O
HO
OH
OH
8
N
O
HO
O
H
H
HO
O
S
4
HO
O
Zetekitoxin AB
Lycojaponicumins A
Alsmaphorazine A
Pyrinodemin A
O
OH
O
Me
H
O
O
N
H
O
O
O
N
H
O
N
O
OH
O
H
O
H
O
Me
HO
MeO
O
H
N
OMe
OH
O
Flueggine A
Dactylicapnosinine
Pyridomacrolidin
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Figure 1. Selected Examples of Naturally Occurring Isoxazolidine-containing
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Compounds.
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Visible-light catalysis is drawing increasing attention in the chemistry discipline for its
intrinsic mildness and environmental friendliness.4 Our group has a long-lasting interest
in developing photocatalyzed novel and practical synthetic methodologies for the easy
access to molecular structures of agrichemical, pharmaceutical or material interests,5
among which we paid special attention to the synthesis of heterocycles. Several
pioneering works on photocatalytic synthesis of isoxazolines have already been reported.
A concise [3+2] cycloaddition reaction between hydroxyamines and alkenes under
visible-light photocatalysis was firstly reported by Reuping et al. in 2014, the essence of
which is the photocatalyzed in situ formation of nitrones from hydroxyamines.6 The Xia
group developed an efficient visible-light-mediated anti-regioselective 1,3-dipolar
cycloaddition reaction between nitrones and oxidizable styrenes or aliphatic alkenes.7
Xiao et al. succeeded in generating sulfonamidyl radicals by visible-light irradiation for
intramolecular alkene hydroamidation to access to isoxazolidine scaffold.8 From
substituted salicylic nitrones, the Moura-Letts group synthesized chromenoisoxazolidines
via visible light photocatalysis.9 It is worth noting that all these strategies explored the
classical 1,3-DC or cyclization of hydroxylamine pathway. Based on our previous works
on the chemistry of α-amino radicals generated by photo-induced oxidative
decarboxylation of amino acids,5d,5f-h we envisioned that the initial radical intermediate
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resulted from the addition of α-amino radicals to alkenes could be trapped by reactive
oxygen species to give an alkyl peroxide intermediate, which upon intramolecular
oxidation reaction could establish the N-O linkage of the desired isoxazolidine ring.
Herein, we report a novel access to isoxazolidines from N-aryl glycines through visible-
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light catalyzed difunctionalization of alkenes (Scheme 1b).
a. Previous Work on Photocatalytic Synthesis of Isoxazolidines
R1
R1
R1
R1
Z
Z
N
Y
Y
R2
or
O
R2
b
a
N
R5
O
R4
R4
R2
R4
R3
R3
Cyclization
1,3-DC
R4
R3
Y = O, Z = NH;
Y = NH, Z = O;
R3
b. This Work
R1
OH
R2
R1
R3
Ar
N
O
O
R2
R1
R2
Ar NH
H
N
COOH
Ar
Cyclization
DPZ, air, hv
- CO2
R3
R3
Difunctionalization
Scheme 1. Previous Works and Our Protocol
Our investigation started with N-phenyl glycine 1a as the nitrogen source and
itaconimide 2a as the radical acceptor (Table 1). To our delight, isoxazolidine 3a was
obtained in 22% yield when dicyanopyrazine-derived chromophore (DPZ)5m was applied
as the photocatalyst and irradiated with a 3 W blue LED for 24 h in DCM under an ambient
atmosphere. The structure of 3a was confirmed by X-ray crystallography. Polar solvents
(MeCN, for an example), usually rendered better solubility of glycine, but gave poorer
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product yields (see the supporting information for more detailed condition screenings).
Water seemed to have a favorable effect, as when the reaction was performed in MeCN-
H2O (4 : 1), a 33% yield could be obtained (entry 4). When LiPF6 was applied as an
additive together with more added radical acceptor (General Condition B, 2.0 equivalent
of alkene 2a), the yield of isoxazoline was further improved to 59% (entry 7). DCE turned
out to be another good alternative solvent for this reaction, affording product in similar
yield and with less polar side products (entry 5). Further optimization showed that
Mg(OTf)2 was the best additive for DCE solvent system. Finally, when 2.0 equivalent of
glycine 1a was used, the reaction performed in DCE (General Condition A) could afford
isoxazolidine 3a in an isolated yield of 61% (entry 9). When the reaction was performed
under the atmosphere of oxygen, only very polar substances was detected at the baseline
of TLC plate, with itaconimide 2a remained largely untouched (entry 10). Only trace
product could be observed when DPZ was unavailable (entry 11) or the reaction was
performed in the dark (entry 12) thus underlining a photocatalyzed transformation.
Table 1. Optimization of the Reaction Conditionsa
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O
O
MeO
MeO
N
N
CN
CN
S
Ph
O
S
H
N
N
COOH
+
N
N Ph
Ph
Ph
DPZ (0.1 mol %)
O
additive (0.2 equv.)
solvent (0.1 M), rt, 24 h
3 W blue LED
O
2a
1a
(0.02 mmol)
3a
(X mmol)
entry
1a (X mmol) additive
solvent
yieldb
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1
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.04
0.04
0.04
0.04
0.04
n/a
DCM
22
15
0
2
n/a
Tol
3
n/a
MeCN
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4
n/a
MeCN:H2O = 4 : 1
33
33
43
59
66
61
0
5
n/a
DCE
6
LiPF6
MeCN:H2O = 4 : 1
7c
LiPF6
MeCN:H2O = 4 : 1
8d
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
DCE
DCE
DCE
DCE
DCE
9d,e
10d,f
11d,g
12d,h
trace
trace
aReaction conditions: 1a (X mmol), 2a (0.02 mmol), DPZ (0.1 mol %), additive (0.2
equiv.), solvent (0.2 mL), 3 W blue LED, 24 h, rt. bDetermined by crude NMR with 1,3,5-
trimethoxybenzene as the internal standard. c0.04 mmol of 2a added. dReaction time was
extended to 48 h. eIsolated product yield. fUnder O2. gWithout DPZ. hIn the dark.
With the optimal reaction conditions in hand, we examined the substrate scope for both
the amino acids and the alkenes (Table 2). While N-aryl glycines with alkyl or weak
electron-withdrawing substituents on the aryl ring are well tolerated (3b – 3f), amino acids
with 2-alkyl/aryl substitutions gave the desired isoxazolines in only trace amount,
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producing tetrahydroquinoline derivatives as major products via cyclization onto the N-
aryl ring10 (see supporting information for details). Itaconimides with varied N-substituents
constitute the best acceptors for radical addition in this reaction (3g – 3o). Of special note
is that, nonterminal alkenes are also viable substrates (3n, 3o). Acrylamide of piperidine
2, 6-di-one skeleton reacted well and gave 3p in 50% yield. Alkenes with different
activating groups were also compatible. Linear acrylamide (3q), α, β-unsaturated ketones
(3r, 3s) and simple substituted acrylates (3t, 3u) could produce isoxazolidines in moderate
to good yields. Acrylonitrile (3v), however, is a less compatible substrate, affording the
desired heterocycle in only 30% yield. For less successful acceptors, polar substances
derived from the over-oxidation of glycine5f or the trapping of the intermediate radical by
CO2 released from the decarboxylation of glycine dominated (Scheme 2c).
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Table 2. Substrate Scope Studya
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MeO
MeO
N
N
CN
CN
S
R1
R2
R1
Ar
O
S
O
H
N
R3
N
COOH
+
R2
Ar
DPZ (0.1 mol %)
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9
R3
O
air
, 3 W blue LED
R
2
1
(0.1 mmol)
(0.2 mmol)
3
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O
O
N
N
N
N
Ph
Ph
O
, R = 3-Me, 60%
O
3b
3c
3d
3e
3a
, 61%
3a
b
, R = 4-Me, 40%
b
, R = 3,5-Me2, 45%
O
Ph
b
O
, R = 4-Cl, 41%
N
O
b
Ph
N
O
3f
, R = 4-Br, 35%
N
N
Cl
O
O
Ph
O
Me
R
N
O
N
3g
3h
3i
3j
, R = Me, 54%
, R = Cl, 59%
, R = F, 62%
3k
, 72%
O
Me
Me
, R = OMe, 54%
O
3l
, 51%
Ph
O
N
O
Ph
Ph
O
O
N
N
N
Ph
O
N
O
O
N
R
Ph
O
3n
3o
, R = Me, 71%, dr 20:1
, R = nPr, 59%, dr = 2.2:1
3p
3m
, 50%
, 60%
Me
Ph
Ph
O
Ph
Ph
O
O
N
N
N
N
CONHPh
O
3s
O
c
3q
, 85%
3r
, 66%
, 55%
Ph
O
O
Me
Ph
O
N
N
CO2But
CN
CO2Me
3v
, 30%
3t
, 48%
3u
, 50%
aFor 3a and 3g – 3o, General Condition A: 1 (0.2 mmol), 2 (0.1 mmol), DPZ (0.1 mol
%), Mg(OTf)2 (0.2 equiv.), DCE (1.0 mL), 3 W blue LED, 48 h, rt; for 3b – 3f and 3p – 3v,
General Condition B: 1 (0.1 mmol), 2 (0.2 mmol), DPZ (0.1 mol %), LiPF6 (0.2 equiv.),
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MeCN-H2O (4 : 1, 1.0 mL), 3 W blue LED, 48 h, rt. bThe reaction was conducted at 10 oC.
cThe corresponding N-Boc protected acrylamide as radical receptor.
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To gain more insights into the reaction mechanism we carried out a series of
mechanistic studies. The 1, 3-dipolar cycloaddition between nitrones and styrene has
been well documented.11 The fact that styrene failed to react with N-aryl glycine under
standard conditions to afford isoxazolidine 5 (Scheme 2a) precludes the possibility of a
nitrone intermediate and thus a 1, 3-dipolar cycloaddition pathway. Then we conducted
control experiments to trap possible radical intermediates (Scheme 2b). As already
mentioned in the condition optimization section, when performed under oxygen, without
any isoxazolidine detected, the reaction only produced highly polar substances. Oxygen
is likely to have a stabilizing effect on itaconimide as when the reaction was done under
argon, the alkene was completely consumed, possibly due to polymerization12 with
glycine left untouched. A known scavenger of reactive oxygen species, DABCO,
produced similar results. When TEMPO was added to the reaction, no desired product
was detected, thus indicating that the reaction may involve a radical mechanism. When
the reaction was performed under the atmosphere of mixed 18O2 and N2 (18O2/N2 = 1/4,
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v/v, 1 atm), isoxazolidine was obtained in 58% yield with more than 50% O incorporation,
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while H2 O failed to produce any O labeled isoxazolidine [18O]-3a (Scheme 2c), proving that
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the oxygen atom of the isoxazolidine ring originate from O2 in the air. Fluorescence quenching
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experiments showed that not only N-phenyl glycine (1a) could effectively quench the fluorescence
of DPZ, Lewis acidic salt LiPF6 also has a notable promoting effect (13.8% increase) for this single
electron transfer process (Figure 2a), possibly due to the stabilizing effect of Li+ on the radical
DPZ ∙ ― through coordination
13. While no fluorescence quenching of DPZ by 2a was
anion
observed, fluorescence emission from itaconimide was detected (note the increasing intensity of
fluorescence (I) with the concentration of 2a). LiPF6 also promoted fluorescence emission (49%
increase) from 2a, and thus implied a positive interaction between them (Figure 2b). Mg(OTf)2
has a similar effect (see supporting information for details). Further detailed mechanistic studies
may be needed to elucidate the exact role of Lewis acids in this photocatalytic transformation.
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a. Nitrone trapping
O
Ph
Ph
(0.5 mmol)
O
H
[3 + 2]
std. conditions
A or B
N
+
N
COOH
N
Ph
Ph
Ph
7
8
4
Nitrone,
1a
(0.1 mmol)
5
, 0% yield
9
b. Radical trapping experiments
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O
O
N
Ph
DPZ (0.1 mol %)
3 W blue LED, LiPF6 (0.2 equiv.)
O
H
N
N
COOH +
N
Ph
Ph
Ph
MeCN-H2O 4:1, air, rt, 48 h
O
O
2a
1a
(0.2 mmol)
3a
(0.1 mmol)
Reaction Conditions
Results
air
2a
54% yield, 1.8 equiv. of
consumed, polar side products
O2
Ar
1a
2a
2a
0% yield, 100% of
0% yield, 100% of
0% yield, 100% of
consumed, highly polar products only
1a
1a
consumed,
consumed,
largely remained
largely remained
air, DABCO (2.0 equiv.)
air, TEMPO (2.0 equiv.)
2a
0% yield, 1.25 equiv. of
consumed, polar side products
c.18O labeling experiment
O
O
18O
Ph
H
N
18O labeling conditions
N
COOH +
N
N
Ph
Ph
Ph
O
O
[18O]-3a
2a
1a
(0.2 mmol)
(0.1 mmol)
Labeling Reagent
Results
General Condition
18O2
A
58% yield, 50.1% 18O incorporation
51% yield, 0% 18O incorporation
H218O
B
Scheme 2. Mechanistic Studies.
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a.
b.
2
1.5
1
1.2
1
0.5
0
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0
0.01 0.02 0.03 0.04 0.05
0
0.01 0.02 0.03 0.04 0.05
1a (M)
2a (M)
Figure 2. Stern–Volmer quenching experiment of DPZ by 1a (a) and 2a (b) in the presence
( ) and absence ( ) of LiPF6 (0.2 M).
Based on mechanistic study results above, a photo-induced alkene difunctionalization
process was proposed herein (Figure 3). On irradiation with a 3 W blue LED (450 nm),
photocatalyst DPZ is promoted to its excited state (Et(S*/ ∙ ― ) = +0.91 V vs. SCE in
S
CH2Cl2)5 and then gets reduced, with the assist of Lewis acid LiPF6,13 by N-aryl glycines
(Ep = +0.52 V vs. Ag/AgCl in CH3CN for N-phenyl glycine)5d,5f-h to radical anion complex
DPZ ∙ ― ∙ Li +
. Oxygen in the air acts as the oxidant to bring this reduced photocatalyst to
its ground state with the releasing of one molar of superoxide radical. Nitrogen radical
cation compound A is known to undergo decarboxylation readily to afford an α-amino
radical B.5d,5f-h The conjugate addition of B to activated alkenes is aided by Lewis acidic
metal ions such as Li+ or Mg2+ to generate a relatively stable α-carbonyl radical C, which
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on coupling with superoxide radical gives peroxide D. Intramolecular oxidation of aryl
amine establishes the N-O bond in a straightforward manner to afford isoxazolidines 3.
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Ar
O
Ar
Ar
O
H+
HN
N
NH
Li+
O
N
DPZ*
Ph
O
COOH
Ph
N
O
O
MeO
MeO
N
N
CN
CN
S
H2O
1
S
Isoxazolidine 3
D
SET
O
O
DPZ
N
O
Li
Ph
Ph
O2
O2
H
SET
N
Ar
Li
O
-H+, -CO2
DPZ
Li
H
Ar
N
N
NH
Ar
O2
COOH
A
O
C
B
Figure 3. Proposed Mechanism.
To demonstrate the potential application of this method, the model reaction to access
3a was attempted on a 1.0 mol scale with both reactivity and yield maintained well
(Scheme 3). It was found that the N-O bond of 3a could be readily cleaved via reduction
by zinc in acetic acid, and a subsequent cyclization was experienced, leading to the
valuable γ-lactam 6, which is the core structure of a large number of natural and non-
natural compounds with a broad spectrum of bioacitivities.14
O
O
H
2a
Ph
(280.5 mg, 1.5 mmol)
O
Ph
O
OH
Zn/HOAc
rt, 8 h
N
COOH
N
N
Ph
N
LiPF (0.2 equiv.)
DPZ (0.1 mol %),
6
Ph
N
MeCN-H2O 4:1, rt, 3 days
3 W blue LED
1a
(150 mg, 1.0 mmol)
H
O
-Hydroxy- -Lactam 6
, 90%


3a
(
, 185 mg, 60%)
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Scheme 3. Scale Up Reaction and Ring-Openning of Isoxazoldine.
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In summary, we have developed a novel access to isoxazolidines which are noted for
their unique pharmaceutical bioactivities and significant role as synthetic intermediates
for amino alcohols. This transition-metal free strategy, featuring photo-induced aerobic
difunctionalization of activated alkenes and oxidative decarboxylation of naturally
abundant amino acids to generate α-amino radicals, is marked for its environmentally
friendliness, high reaction economy, and enhanced synthetic efficiency. Furthermore, this
is the first synthesis of isoxazolines without following the routine 1, 3-dipolar cycloaddition
or hydroxylamine cyclization strategy and serves as a useful alternative method for the
preparation of this important heterocyclic scaffold. The reductive ring-opening of
isoxazolidines readily affords important γ-lactams, thus greatly expanding the application
of this green, mild and efficient approach.
AUTHOR INFORMATION
Corresponding Author
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*E-mail: chmjzy@henu.edu.cn; weiguo0325@henu.edu.cn
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information.
Supporting Information Available: [General information, optimization results, general
procedures, characterization data, and spectra (PDF); X-ray data (CIF).] This material is
available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We are grateful for the grants from NSFC (21072044), and Henan Province
(14IRTSTHN006, 152300410057, 15A150006, 182102310246).
REFERENCES
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Graphical Abstract
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R2
O
H
Ar
N
COOH
R1
CO2
H2O
N
DPZ
Ar
R2

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R3
O2
Isoxazolidines
R1
R3
air, rt
Up to 85% yield
Nitrone Free Straightforward Economic



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