An Approach to α- and β-Amino Peroxides via Lewis Acid Catalyzed Ring Opening-Peroxidation of Donor-Acceptor Aziridines and N-Activated Aziridines

Article abstract of DOI:10.1002/adsc.202000815

Site-selective ring-opening process of two different aziridine classes with hydroperoxide is described herein that provides access to various α- and β-amino and α-(imino)-peroxy compounds. This strain-release-driven peroxide addition to aziridines represents an alternative approach for entries to biologically significant heteroatom substituted organic peroxides and complements existing methods in the field. The peroxide products obtained by this method displayed a different reactivity during peroxide-specific rearrangement processes promoted by either acid or base. Mechanistic studies and useful synthetic elaboration of the products have also been presented. (Figure presented.).

Full text of DOI:10.1002/adsc.202000815

Title: An Approach to α- and β-Amino Peroxides via Lewis Acid
Catalyzed Ring Opening-Peroxidation of Donor-Acceptor
Aziridines and N-Activated Aziridines
Authors: Jaideep Saha, Kuldeep Singh, Pramod Kumar, Chenna
Jagadeesh, Manveer Patel, and Dinabandhu Das
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
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000815
Link to VoR: https://doi.org/10.1002/adsc.202000815

Advanced Synthesis & Catalysis
10.1002/adsc.202000815
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
An Approach to α- and β-Amino Peroxides via Lewis Acid
Catalyzed Ring Opening-Peroxidation of Donor-Acceptor
Aziridines and N-Activated Aziridines
a†
a†
a
a
Kuldeep Singh, Pramod Kumar, Chenna Jagadeesh, Manveer Patel, Dinabandhu
b
a
Das, Jaideep Saha *
a
Division of Molecular Synthesis & Drug Discovery, Centre of Biomedical Research (CBMR), SGPGIMS Campus.
Raebareli Road, Lucknow-226014, Uttar Pradesh. India
Email: jaideep.saha@cbmr.res.in, jdsaha2000@gmail.com
School of Physical Sciences, Jawaharlal Nehru University, New Delhi, India
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Site-selective ring-opening process of two method displayed a different reactivity during peroxide-
different aziridine classes with hydroperoxide is described specific rearrangement processes promoted by either acid or
herein that provides access to various α- and β-amino and α- base. Mechanistic studies and useful synthetic elaboration
(
imino)-peroxy compounds. This strain-release-driven of the products have also been presented.
peroxide addition to aziridines represents an alternative
approach for entries to biologically significant heteroatom Keywords: Donor-Acceptor aziridine; N-Activated
substituted organic peroxides and complements existing aziridine; Organic Peroxides; N-(α-Peroxy) Linkage
methods in the field. The peroxide products obtained by this
(
Scheme 1a).[6a-f] Different iteration of this reaction
Introduction
manifolds were disclosed in past years.
Organic peroxides have secured an important place in
the realm of organic synthesis and medicinal
chemistry owing to their potential and tested
[1-2]
bioactivities for
a
range of pathologies.
Compounds bearing peroxide moiety occurs naturally,
which has spurred the interest for the development of
synthetic variants. Till date, several synthetic
peroxides have been developed with potential anti-
malarial,[
2j]
anti-cancer,
[3]
anti-HIV
[4]
and anti-
[5]
hepatitis B activity. Among the α-heteroatom
substituted peroxides, those having a N-(α-peroxy)-
[6]
linkage, is receiving greater attention. Such linkage
is featured in natural products such as verruculogen,
dioxetanone[ and also in other synthetic peroxides
Figure 1. Natural products and bioactive compounds with
peroxy and α-nitrogen substituted peroxy linkage.
7]
[6d]
with antimalarial or anti-cancer activity (Figure 1).
This underscores the development of better methods
for functionalized α-N-peroxide scaffolds, to fully
evaluate the breadth of their prospective utility in
biological contexts. It is important to note that, while
radical based approaches, such as olefin
carboperoxidation have been widely explored for the
preparation of a range of organic peroxides, these
were however least suited for α-heteroatom
containing motifs. Alkylperoxide or hydrogen
peroxide addition to imines at large remains as a
powerful means to prepare N-(α-peroxy) compounds
For instance, Toniolo reported an interesting
development for the synthesis of peptide dialkyl
[6c]
peroxides,
which proceeded with the in situ
generation of an imine residue. In 2010, Antilla and
co-workers reported the entries to chiral α-amino
[6e]
[8]
peroxides via chiral phosphoric acid catalysis.
Apart from such reliance on the imine-based
strategies, some important multicomponent approach
to N-(α-peroxy) compounds have also appeared
(Scheme 2a). Ghorai and co-workers reported the
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
assembly of different α-azido-peroxide through a
three-component reaction.[ Similar strategy was
later followed by Wang and Lai for the construction
site-selective ring opening hydroperoxidation method
of two types of aziridines (i.e., D-A aziridine and N-
activated aziridine, Scheme 1c). The α-amino
peroxides obtained from D-A aziridines further
served the resort for accessing imino (α-peroxy)
compounds, which could be regarded as another
novel and structurally interesting peroxide class.
6g]
[6h]
of
N-(α-peroxy)indole/carbazoles.
These
transformations proceeded via peroxy-carbenium ion
intermediate, which was then captured through
different N-centred nucleophiles. Very recently,
reaction of α-amido sulfones with dialkyl zinc was
[6i]
explored for the synthesis of α-amino peroxides.
protocol based on Curtius rearrangement was
developed by Dussault where peroxyalkanoyl azides Results and Discussion
A
[6j]
were transformed into α-N-peroxide moiety.
Another recent report from Waser’s group showcased
selected entries to N,O-peroxyacetal from
aminocyclopropanes via oxidative ring-opening
strategy with hydroperoxides.[
Lewis acid catalyzed nucleophilic ring-opening
reactions of N-activated aziridines are relatively well
studied. In this case, Lewis acid coordination at the
nitrogen site facilitates C-N bond cleavage and leads
6k]
[13]
to β-amino functionalized compounds. Conversely,
the dicarbonyl moieties present on a donor-acceptor
(a) Hydroperoxide addition to imines
(
D-A) aziridine system function as the preferential
O
N
O
H
NH
Lewis acid binding site. As a result, an alternative
ring opening process becomes viable through C-C
bond cleavage. To check the feasibility of ring-
opening reaction of D-A aziridine with
hydroperoxides, we commenced our investigation
with compound 1a and tert-butyl hydroperoxide in
presence of various catalysts and solvents (Table 1).
O
O
(b) Hydroperoxide addition to in situ generated peroxy-carbenium intermediate
O
Nu = “N”
N
O
O
+
O
H
O
H
O
LA or H+
O
via
(c) Site selective ring-opening peroxidation of aziridines (This study)
Table 1. Optimization Studiesa
O
O
O
O
H
O
O
H
O
R3
O
R3
N
R3
R2
O
R3
O
R1
R2
Cu(II)-cat
Sc(III)-cat
R1
R1
R2
tBu
N
R1
R2
N
Ts
HN
C-N bond
cleavage
C-C bond
cleavage
O
N
CO Et
O
CO2Et
CO Et
2
cat
+ tBuOOH
CO2Et
N
solvent
2
Ts
1a
2a
3aa
Scheme 1. Literature strategies and our approach for the
synthesis of α- and β-amino peroxides.
Entry
1
2
3
4
5
6
7
Cat.
[mol%] TBHP Solvent Yield
[%]b
[
equiv]
-
-
-
-
10
10
10
10
10
10
10
10
10
10
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
0c
d
38
35
We recently disclosed a catalytic method for
Cu(OTf)
Mg(OTf)
Zn(OTf)
Sn(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
TfOH
2
20
20
20
20
20
10
20
20
20
20
alkylperoxide addition to donor-acceptor (D-A)
c
cyclopropanes.[
9]
2
0
Inherent ring-strain of D-A
2
25
c.m
77
60
45
cyclopropane largely facilitated the process in
presence of a Lewis acid and thus provided a gateway
to functionalized peroxides. Some entries to elusive
e
2
3
3
3
3
3
8
9
10
α-amino peroxides were also made in the study. In
light of this work,[10] we envisaged the possibility for
[11]
Toluene 66
DCM
DCM
employing donor-acceptor (D-A) aziridines
similar peroxidation and was prompted by the notion
that, it could deliver α-amino alkyl
for
1
1
1
2
35
c
10
0
peroxides/hydroperoxides under suitable conditions.
Aziridines generally represent a valuable source for
azomethine ylide or N-containing 1,3-dipole. A
regioselective addition process therefore could
leverage the access to various nitrogen-containing
peroxides. Interestingly, despite the large application
of aziridines in the domain of organic synthesis over
several decades, their utility in the preparation of
amino-peroxides remained least explored. Only
a
Reaction conditions: 1a (1.0 equiv.), 2a (5-10 equiv) in 5-
b
6
M decane solution, 3-4 h at room temperature. Isolated
c
d
yields. Unreacted starting material. 70% aqueous solution
of TBHP was used. Complex mixture.
e
Aziridine 1a was found to be completely unreactive
when TBHP in 5-6 M decane solution was used in
DCM. Pleasingly, aqueous TBHP solution was
effective in promoting the reaction to desired product
recently,
a
report on the ring opening of
spiroaziridine oxindoles has appeared that furnished
oxindole-embedded β-amino peroxides.[12] With our
continued interest for developing novel peroxidation
strategies, we herein present metal triflate-catalyzed
3
aa. The reaction however was sluggish and afforded
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
R5
O
the product in 38% yield only (entry 2). We surmised
that catalytic Lewis acid activation of compound 1a
would facilitate both, the reaction rate and efficiency.
R2
N
LA
O
R3
R3
O
H
+
O
R5
solvent
CO2R4
R1
CO2R4
R1
N
1
2
R2
3
Accordingly, we employed 20 mol% Cu(OTf) in the
2
Cl
reaction which in fact provided 3aa in shorter
reaction time albeit subtle improvement in efficiency
was noted (entry 3). Other Lewis acids such as
CO2Et
O
CO Et
2
CO Et
2
O
O
O
tBu
O
N
S
CO2Et
tBu
CO Et tBu
CO2Et
N
CO Et
O
N
S
2
O
N
S
2
CO Et
O
O
O
O
O
O
tBu
O
2
Mg(OTf)
2
, Zn(OTf)
2
, Sn(OTf)
2
either failed or
O
S
O
Me
showed no improvement (entries 4-6). Drawn from
our previous experience that rare earth metal triflates
exhibit better reactivity and compatibility profile with
3
da (70%)
Me
Br
3
aa (70%, 1g scale)
3ba (60%)
3ca (66%)
R1
Me
hydroperoxides, Sc(OTf)
3
was next evaluated.
CO2R2
CO2Et
2
CO Et
Pleasingly, a dramatic improvement in both, reaction
rate and yield was achieved (entry 7). Appearance of
tBu O
O
N
S
CO2R2 tBu O
tBu
O
N
S
CO2Et
O
O
N
S
CO2Et
O
1
O
O
O
O
O
1
two singlet at δ 6.32 and 4.56 ppm in H-NMR was
characteristic of the site selective C-C bond cleavage,
which was further corroborated via X-ray crystal
structure analysis of a related structure 3ea (vide
infra). Lowering of the catalyst loading to 10 mol%
slowed the reaction and resulted in a lower yield of
product and greater formation of impurity (entry 8).
Altering the solvent choice from DCM to THF was
detrimental whereas toluene turned out to be an
effective alternative (entries 9-10). Lowering the
equivalence of TBHP also had detrimental effects
Me
Me
3ha (60%)
Me
3ea (62%)
2
3ea
3fa R = H, R = Me (73%)
ga R =Me, R = Pr (51%)
1
2
i
3
X
Me
CO Et
CO2Et
CO2Et
2
CO Et
2
CO2Et
CO Et
tBu O O
tBu O
CO2Et tBu O
O
N
S
O
N
S
O
N
S
2
CO Et
tBu
O
N
S
2
O
O
O
O
O
O
O
O
3ia X= F (72%)
Me 3ja X= Cl (70%)
3ka X= Br (56%)
Me
3la (67%)
Me
3ma (85%)
Me
3na (75%)
Me
Me
(
entry 11). Use of catalytic TfOH did not furnish the
CO2Et
CO2Et
CO2Et
R
R2
CO2Et
desired product (entry 12), indicating an important
role of the metal triflate in the transformation.
With the optimized sets of reaction conditions, we
next surveyed the substrate scope of different D-A
aziridines (Scheme 2).
O
O
O
H
O
N
S
O
N
S
CO2Et tBu
O
N
R1
CO2Et
2
H
O
N
S
O
CO2Et
O
O
Me
O
O
O
O
1
a
3oa R= n-C3H7, R = Ts, R = CO2Et (0%)
i
1
2
a
3
pa R= Pr, R = Ts, R = CO2Et (0%)
1
2
a
3qa R= H, R = Bn, R = H (0%)
Me
Me
Me
3ec (59%)
3eb (70%)
3
ac (56 %)b
b
Scheme 2. Substrate scope with D-A aziridines. Reaction
conditions: 1 (1.0 equiv), 2 (10.0 equiv), Sc(OTf) (0.2
equiv) in DCM. Unreacted starting materials. Reaction
was performed with ethereal solution of H
3
a
b
2
2
O .
Different sulfonyl group at the nitrogen center of
aziridine proved to be highly efficient substrate in the
reaction (3ba-3da), whereas, free NH or N-alkyl
substitution were futile. Next, influence of various
substituted phenyl ring as donor group was
investigated. Weakly electron donating and
withdrawing substituents (e.g., p-methyl, p-isopropyl,
p-halogens, m-methyl etc.) afforded smooth
conversion to desired products 3ea-3la. Conversely,
strong directing groups on the ring (e.g., p-OMe, p-
CN) produced only trace amount of hydroperoxide
addition products along with other intractable product
mixture (not shown). Importantly, substrates with
extended π-aromatic framework such as α- and β-
naphthyl afforded superior results (3ma-3na).
Variation in the alkyl hydroperoxide was tolerated as
exemplified with the use of methylcyclohexyl
hydroperoxide (3eb). We found that alkyl groups at
the donor end of D-A aziridine display poor reactivity
(
3oa-3pa). It was also the case when unsubstituted
aziridine with a monoester group (3qa) was
employed. This alludes the importance of the geminal
dicarbonyl group at acceptor side.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
After accessing the above series of α-amino alkyl
peroxides, we turned our attention to prepare α-amino
hydroperoxides (i.e., with a –OOH group). When
3
0% aqueous H
2
O
2
solution was used for the addition
of hydrogen peroxide to D-A aziridine, it provided
unsatisfactory results. However, ethereal H
2
O
2
solution (10 equiv) proved effective and desired
products were obtained in moderate yields (3ac, 3ec).
It should be noted that, reactions involving H
O
2 2
produced higher amount of impurity and entailed a
difficult purification step, compared to those with
TBHP. The current protocol is amenable to gram
scale preparation as demonstrated in the preparation
of compound 3aa (70%).
Scheme 4. Hock-type rearrangement under acidic
conditions.
However, the observed reactivity of compound 3
differed strikingly from that of γ-peroxycarbonyls. In
this case, cleavage of the C-N bond occurred in
preference to aryl migration at the peroxy bond.
Fragmentation of compound 3ea into p-tolualdehyde
[16]
(
4) and compound 5 (1:1) was observed and the
process might occur via formation of a peroxy-
carbenium intermediate.
[17]
The Kornblum-DelaMare rearrangement was next
investigated on 3aa in presence of DBU, which
produced no reaction. However, with the aid of 50
t
[18]
mol% BuOK,
a new product formation was
observed, which was characterized to be α-N(imino)-
peroxy compound 6a (Scheme 5). Importantly, no
trace of Kornblum-DelaMare rearrangement could be
detected in this case. This could be attributed to
higher acidity of malonate proton, which triggered a
Scheme 3. Peroxidation of D-A aziridines with ketoester
or diketone acceptor group.
faster 1,2-elimination of tosyl group, superseding the
To our surprise, when a keto-ester moiety was present
at the acceptor side of D-A aziridine (Scheme 3), the
ring-opening pattern followed a different course from
those with the diester group. The 2D-NMR studies
confirmed the resulting structure to be a β-amino
peroxide, 3ra. This could essentially result from
either C-N bond cleavage during hydroperoxide
addition stage or by other distinct mechanism (vide
infra). Nonetheless, the structural feature of the
compound is particularly noteworthy, as it represents
an amino acid derivative with a quaternary centre and
a peroxy motif. Similar trend was also noted for
acetylacetone-derived (diketone) substrate (3sa).
[19]
proton abstraction at benzylic position.
The
reaction appeared to be general and was applicable to
a range of substrates with different substitution on the
phenyl ring and variation of dicarbonyls (6a-6f). It is
to be noted that, compound 6 represents a new class
of α-N-peroxy compounds.
tBu
tBu
O
CO2Et
CO Et
O
O
O
CO2R
CO2R
tBuOK (50 mol%)
THF
O
CO2R
CO2R
N
2
Ar
N
Ar
N
Ts
Acid promoted rearrangement of organic peroxides
Ts
3
(
not observed)
6
(
i.e., Hock-type rearrangement) has been largely
tBu
tBu
tBu
explored for important downstream synthetic
transformations. In this context, γ-peroxycarbonyls
have lent themselves for the preparation of
O
O
O
O
CO2Et
CO2Et
O
CO Et
O
CO2Et
N
CO2Et
2
N
N
CO Et
2
Me
Br
6
a (57 %)
6b (60 %)
6c (55 %)
tBu
functionalized furans, pyrroles, carbazole or dibenzo-
tBu
tBu
xanthene derivatives.[
9,14]
Based on the structural
O
O
O
O
CO2Et
CO2Et
O
CO2Et
CO2Et
O
2
CO Me
similarity of γ-peroxycarbonyl to α-N-peroxide, we
considered to study compound 3 under Hock-type
rearrangement conditions (Scheme 4) in presence of
TfOH.[
N
N
N
2
CO Me
Me
6d (58 %)
6e (51%)
6f (62%)
15]
Scheme 5. Reaction of peroxide 3 under basic conditions.
We next planned to evaluate hydroperoxide
addition to N-activated aziridines under Lewis acid
activation (Scheme 6). Of note that the standard
reaction
conditions
with
Sc(OTf)
3
proved
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
unsatisfactory in this case.[20] Following few
presents an alternative route for accessing such
[21]
optimization trials, Cu(OTf)
2
appeared as the most
moiety.
In another reaction, compound 8ca was
effective catalyst and rendered the desired product
transformed into 3-hydroxyindoline derivative 10
(78%) via intramolecular N-arylation.
8
aa in 82% yield. Influence of various substituents on
the aromatic ring was next tested. It was found that
We next performed selected experiments that
shed light on the mechanistic aspects of ring-opening
peroxidation of aziridines. Ligand exchange of
electron neutral or halogenated substrates (8ba-8da,
8
ga) provided superior results in comparison to
[22]
substrates with electron-withdrawing substituents on
Sc(OTf) with peroxides was studied in the past.
3
the phenyl ring (8ea-8fa).
To gain insights on the nature of scadium species
involved in the present study, we monitored the
4
5
peroxidation reaction with Sc-NMR spectroscopy
(
Figure 2). While Sc(OTf) alone was insoluble in
3
DCM, coordination with D-A aziridine (1a) produced
a broad signal at δ 15.5 ppm (Fig. 2a). An upfield
4
5
Sc-NMR signal (δ 3.5 ppm) was recorded when
Sc(OTf) (20 mol%) was added to a solution of 1a
3
and TBHP and this was independent to the order of
addition of reagents (Fig. 2b). A similar resonance
was detected when Sc(OTf)
TBHP (5-6 M in decane) were taken together (Fig.
c).
3
and 10 equivalent of
2
Ts
N
tBu
O
Sc(OTf)3
O
CO2Et
CO Et
2
+
tBuOOH
Ph
CO Et
Ph
N
CO2Et
3aa
2
Ts
1a
(c)
δ = 3.7 ppm
(b)
δ = 3.5 ppm
δ = 15.5 ppm
Scheme 6. Hydroperoxide addition to N-activated
aziridines. Reaction conditions: Aziridine 7 (1.0 equiv),
hydroperoxide (2, 10.0 equiv), DCM (2.0 M), rt.
(a)
This reactivity trend was in accord to other reports
with nucleophilic ring opening of this class of
aziridines. Methylcyclohexyl and tetrahydropyranyl
45
Figure 2. Sc-NMR study of peroxidation reaction of D-A
aziridine. Experiments: (a) Aziridine 1a, Sc(OTf) (0.2
equiv) in DCM. (b) Aziridine 1a, tert-butyl hydroperoxide
(10.0 equiv), Sc(OTf) (0.2 equiv). (c) Tert-butyl
hydroperoxide (10.0 equiv), Sc(OTf) (0.2 equiv) in DCM.
3
(
THP) hydroperoxide could also be added, albeit
some variation in efficiency was observed (8ab, 8bb,
ad). Aziridine with alkyl group at C2 position was
3
8
3
an incompetent substrate (8ha). When we turned to
add hydrogen peroxide to compound 7a, only 1,2-
amino alcohol could be isolated from the reaction
mixture. Though the hydrogen peroxide addition
product could be detected in MS analysis, it alludes
that the product is unstable and prone to
disproportionation.
Collectively, these data may suggest the formation of
an alkylperoxy-scandium species, Sc(III)L
catalytic cycle.
n
in the
Based on literature precedents and our own
experiments, mechanistic proposal for
a
hydroperoxide addition to D-A aziridine via C-C and
C-N bond cleavage is outlined in Scheme 8a. Initially,
ring-opening of D-A aziridine 1a to azomethine ylide
A via C-C bond cleavage, assisted by Sc(III)-species
is proposed. It then undergoes nucleophilic addition
by TBHP at C3 and subsequently the proton capture
from C2 and dissociation of Lewis acid from B
furnishes compounds 3 (i.e., representative of
products in Scheme 2). While formation of β-amino
peroxides (such as 3ra, 3sa) could also follow a
similar path up to the stage of intermediate B, a C-N
cleavage could occur at this point for the substrates
with a ketone residue, and leads to C (path a). A
reunion through addition of enolate on peroxy-
Scheme 7. Follow-up chemistry with β-amino peroxides.
The β-N-peroxy compounds were next subjected to
synthetic
elaboration.
Kornblum-DelaMare
rearrangement of 8aa furnished aminoketone
derivative 9 in 62% yield (Scheme 7). This reaction
5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
room temperature. Progress of the reaction was monitored
via thin layer chromatography (TLC) and the reaction was
stopped upon complete disappearance of the starting
materials (ca. 2-3 h). The reaction mixture was then diluted
with DCM (2.0 mL) and successively with water (2.0 mL)
and brine (2.0 mL) solution. Combined organic layer was
carbenium would produce the rearranged isomers
3ra/3sa. Fragmentation of compound 3ea as shown
earlier in Scheme 4, further lends support to this path
with the C-N cleavage. Although, formation of
3
ra/3sa via C-N cleavage directly from D-A aziridine
during hydroperoxidation could be another viable
pathway (path b). On the other hand, Cu(OTf)
2 4
then dried over anhydrous Na SO and filtered. Solvents
were removed under reduced pressure (while maintaining
o
2
the bath temperature at ~ 30 C) and the crude product was
catalyzed hydroperoxide addition of enantiopure
aziridine (R)-7a (>99% ee) furnished the expected
product 8aa in 78% yield, albeit with an erosion in
the enantiomeric excess (68% ee) (Scheme 8b). This
purified by silica gel flash column chromatography to
obtain various peroxidation products 3.
Procedure for the Preparation of α-N(imino)-peroxy
Compounds (6a-6f): To a solution of α-N-peroxy-
containing compounds 3, (0.04 -0.065 g) in dry THF (0.2
data suggested that the reaction didn’t exclusively
2 –type pathway.[
23]
t
o
M) under argon was added BuOK (50 mol%) at 0 C and
the reaction mixture was stirred at room temperature. The
reaction was stirred for 5-6 h until the disappearance of the
starting material was observed by TLC. The reaction was
diluted with EtOAc (2.0 mL), and successively washed
with water (2.0 mL) and brine (2.0 mL). Combined organic
follow a S
N
(a)
C-C bond
cleavage
Y
Ts
Ar
R‘
O
O
N
O
ScIIILn
RO
H
O
A
H
O
2 4
layer was then dried over anhydrous Na SO and filtered.
Y
ScIIILn
ScIIILn
R’
R’
Solvents were removed under vacuo (bath temperatuer <30
Ts
N
Ar
1
O
o
COY
O
O
O
COY
C) and the crude product was purified by silica gel flash
Ar
O
N
Y= OR
(diester)
3
2
1
N
CO2R
3
2
column chromatography to afford α-N(imino)-peroxy
compounds 6a-6f.
Ts OR
B
Ar
CO2R
1
Ts
fragmentation
Y= alkyl
3
Y= alkyl or OR
path b
path a
Y
(
products in Scheme 2)
(ketoester)
R‘
General
Procedure
for
Ring-Opening
O
O
1
HN
Ts
R’
Ar
O
ScIIILn
C-N bond
cleavage
enolate
addition
Hydroperoxidation of N-Activated Aziridines: To a
solution of aziridine 7 (0.1 g) in dry dichloromethane (2.0
M) under argon was added tert-butyl hydroperoxide (10.0
equiv. 5-6 M solution in decane). To this solution was
+
O
O
Ar
3
2
COY
O
HN
Ts OR
RO2C
C
(
3ra/3sa)
(b)
Ts
N
tBuO O
2
added Cu(OTf) (20 mol%) and the reaction mixture was
Cu(OTf)2 (20 mol%)
CH2Cl2
tBuOOH
stirred at room temperature. The reaction was monitored
by thin layer chromatography (TLC) until the
disappearance of the starting materials (ca. 3-5 h). The
reaction was then diluted with DCM (2.0 mL), and
successively washed with water (2.0 mL) and brine (2.0
mL) solution. Combined organic layer was dried over
+
NHTs
(10 equiv)
(R)-7a, >99% ee)
8aa (78%, 66% ee)
Scheme 8. Mechanistic proposal
anhydrous Na SO and filtered. Solvents were removed
2 4
o
under reduced pressure (bath temperature <30 C) and the
crude residue was purified by flash column
chromatography to obtain various β-N-peroxy compounds
Conclusion
8
.
In conclusion, we have developed a new
approach to access various α- and β-nitrogen
substituted peroxy compounds, which is pillared on
the strain-release peroxidation process of structurally
diverse aziridines. Site-selective and complementary
bond polarization of two different classes of
aziridines was achieved under two different Lewis
acid-activation conditions. The ease to perform the
reaction, the substrate scope, and potential to achieve
N-(α-/β-peroxy)-linkage diversity should prove this
method valuable in the context of preparing
compounds with similar pharmacophores. The
amino-peroxides were amenable to further
transformation and rendered important derivatives.
Crystallographic Data: Crystal structure of compound
3
ae was determined by Single Crystal X-ray Diffraction
(SCD) experiment. CCDC 2003419 contains the
supplementary crystallographic data. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Center
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
†These authors contributed equally to this work. J.S greatly
acknowledge the support from SERB, New Delhi
(
ECR/2016/001474. K.S and P.K thank SERB for the National
Post-Doctoral Fellowship award (PDF/2017/000097 to K.S and
PDF/2018/000177 to P.K). D.D thanks DST-FIST for X-ray
facility at SPS, JNU.
4
5
The Sc-NMR study and other control experiments
provided useful mechanistic insights on the overall
ring-opening peroxidation reaction of structurally
different aziridines.
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
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3
as was
monitored by H-NMR whereas, in presence of
Cu(OTf) , only peak-broadening of 7a was observed.
1
2
[
[
[
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Sc(OTf) prior to TBHP addition rendered a complex
mixture with no trace of desired product. Addition of
Sc(OTf) after TBHP afforded desired product in 35%
yield. Aziridine 7a decomposed instantaneously (ca. ~5
3
is crucial for this reaction. Addition of
3
3
8
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Advanced Synthesis & Catalysis
10.1002/adsc.202000815
FULL PAPER
An Approach to α- and β-Amino Peroxides via
Lewis Acid Catalyzed Ring Opening-Peroxidation
of Donor-Acceptor Aziridines and N-Activated
Aziridines
Adv. Synth. Catal. Year, Volume, Page – Page
Kuldeep Singh,† Pramod Kumar,† Chenna
Jagadeesh, Manveer Patel, Dinabandhu Das,
Jaideep Saha*
9
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