1
Introduction
Oxaziridines
constitute a subset of a class of versatile oxidants
whose characteristic feature is the presence of two electronegative
heteroatoms within a strained three-membered ring (Figure 1). Other small organic
heterocycles in this class
include diaziridines
1
and dioxiranes,
2
which have been developed as reagents for a variety
of oxidative transformations. η2-Peroxo and η2-hydroperoxy complexes of various transition
metals are also
members of this class,
3
and these structures
are the active oxidizing species in a broad range of synthetically
useful oxidative transformations, including the Sharpless asymmetric
epoxidation,
4
VO(acac)2-catalyzed
epoxidations,
5
and MeReO3-catalyzed
hydroxylation of unactivated alkanes.
6
Peroxometal
complexes are relevant in biological systems as well; dinuclear μ-η2:η2-peroxodicopper(II)
complexes found within
the active sites of metalloenzymes such as hemocyanin and tyrosinase
have been extensively studied for their role in oxygen metabolism.
7
Figure 1
Representative oxidizing heterocycles with two electrophilic
heteroatoms
within a three-membered ring.
Oxidants within this class are generally used in synthesis
as atom-transfer
reagents; oxidations and aminations of alkanes, alkenes, arenes, amines,
sulfides, phosphines, and alkoxides are typical reactions observed.
8
Despite the diverse range of substrates oxidized
in these transformations, the mechanisms involved are quite similar.
These reactions generally involve a substantially concerted atom transfer
from the oxidant to an organic substrate, driven by the release of
ring strain and by the formation of a strong carbonyl, imine, or oxometal
π-bond.
9
Consequently, reactions
mediated by these oxidants have a propensity to be stereospecific,
and the oxidations proceed without the generation of strongly acidic
or basic byproducts. These features have generated considerable interest
in the development of synthetic methods mediated by this class of
heterocycles.
Oxaziridines, the subcategory consisting of oxygen–nitrogen–carbon
heterocycles, were the first members of this class to be described.
First reported by Emmons in 1957,
10
oxaziridines
can be easily prepared by a variety of procedures on a multigram scale.
Additionally, oxaziridines tend to be significantly more stable than
analogous dioxirane and peroxometal complexes; most simple oxaziridines
can be purified by standard chromatographic techniques or by recrystallization.
They are also amenable to manipulation on the benchtop without precautions
against air or moisture and can be stored indefinitely at reduced
temperatures without noticeable decomposition.
11
Research involving oxaziridines over the past five
decades has
been motivated by the unusual physical properties of these compounds
as well as their distinctive reactivity. The most well characterized
reactivity of oxaziridines is their ability to serve as electrophilic
oxygen atom transfer reagents. Numerous excellent reviews focusing
on this aspect of oxaziridine chemistry have been published,
12
and in deference to the comprehensiveness of
these reviews, we focus largely upon novel oxaziridine-mediated oxygen
atom transfer reactions published within the last 20 years. Within
the past decade, however, the chemistry of oxaziridines has been significantly
expanded and now encompasses many diverse reaction types. In this
review, we will provide a brief background on the synthesis and physical
properties of different classes of oxaziridines, and then offer an
evaluation of the growing body of new synthetic methods developed
that exploit the unique chemistry of oxaziridines.
2
Synthesis and Physical Properties of Oxaziridines
2.1
N-Alkyloxaziridines
Oxaziridines can
be conveniently classified upon the basis of the
identity of their N-substituent, which exerts a significant
effect on their reactivity. The first class of oxaziridines to be
reported were N-alkyl-substituted oxaziridines, initially
synthesized by Emmons in 1957.
10
The standard
method for their preparation involves the oxidation of an imine (e.g., 1) to afford
the corresponding oxaziridine (2).
1
The use of peroxy acids, particularly m-chloroperbenzoic acid (mCPBA), to oxidize
imines as described in Emmons’ initial report continues to
be the most common method for oxaziridine synthesis. Experimental
13
and theoretical
14
studies support a two-step mechanism for imine oxidation (Scheme 1).
Scheme 1
Mechanism of Imine Oxidation by Peracids
In addition to the use of peroxy
acids, a range of other oxidation
conditions has also been applied to transform N-alkyl
imines to the corresponding oxaziridines. The use of cobalt/O2,
15
urea–hydrogen peroxide,
16
in situ generated peroxyimidate,
17
and rhenium–peroxide
18
systems has been successful. Additionally, N-alkyloxaziridine structures can also
be accessed via photochemical
rearrangement of nitrones
19
or ozonolysis
of Schiff bases,
20
albeit with lower yields.
Due to the inherent strain in the three-membered ring and the presence
of an adjacent oxygen atom, the nitrogen stereocenter of N-alkyloxaziridines exhibits
remarkable configurational stability,
21
with barriers of inversion ranging from 25 to
32 kcal/mol.
22
This high barrier of inversion
allows the isolation of the cis and trans diastereomers of N-alkyloxaziridines as
discrete entities at room temperature
and has allowed the synthesis of optically active N-alkyloxaziridines chiral only
at nitrogen.
23
Optically active N-alkyloxaziridines have also
been prepared via photolysis of chiral inclusion complexes of nitrones
in high ee.
24
Catalytic asymmetric approaches
to N-alkyloxaziridines have been reported utilizing
chiral α-bromonitriles and hydrogen peroxide, but the observed
enantioselectivites are generally rather low.
25
The synthesis of fluorinated N-alkyloxaziridines
also generally relies on the use of mCPBA to oxidize
the corresponding imine; however, the preparation of the starting
imines is quite specific. Petrov and Resnati have reviewed synthetic
approaches and applications of a wide variety of fluorinated oxaziridines.
12c
The most widely utilized perfluorinated oxaziridine,
perfluoro-cis-2-n-butyl-3-n-propyloxaziridine 5, is prepared by conversion
of perfluorotributylamine to perfluoro-(Z)-4-aza-4-octene 4 by SbF5 followed by oxidation
with acid-free mCPBA (Scheme 2).
26
The barrier of nitrogen inversion in perfluoro-2,3-dialkyloxaziridines
has not been reported; however, the lack of epimerization of these
compounds at ambient or elevated temperature suggests that the barrier
is higher than 25 kcal/mol.
Scheme 2
Synthesis of Perfluoro-cis-2-n-butyl-3-n-propyloxaziridine
2.2
N-H Oxaziridines
Oxaziridines bearing unsubstituted
nitrogen atoms are generally not
synthesized by standard peracid oxidation methods due to the instability
of N-H imines. Schmitz et al. reported the preparation
of oxaziridine 7 by reaction of cyclohexanone with ammonia
and sodium hypochlorite.
27
A small amount
of the N-chlorocyclohexanimine 8 is
also formed in the reaction, but it does not affect typical synthetic
applications of the N-H oxaziridine. N-Unsubstituted oxaziridines are highly reactive
toward nucleophiles
and are usually formed in situ in inert solvents and reacted further
without additional purification. If chlorine-free solutions of oxaziridine 7 containing
less unreacted cyclohexanone are required, the
compound can be obtained from the reaction of hydroxylamine-O-sulfonic acid with cyclohexanone
and sodium hydroxide.
28
In addition, N-H oxaziridines
have also been obtained via photolysis of hydroxylamines,
29
oxidation of ketimines by peracid,
30
and ozonolysis in the presence of ammonia.
31
2
Optically active N-H oxaziridines
have been prepared from camphor and fenchone by Page
and co-workers.
32
Due to the steric hindrance
around the ketone moiety, the typical routes to access the N-H oxaziridine were unsuccessful.
An alternative sequence
involving nitrosation and rearrangement of oxime 9 followed
by ammonolysis of the resulting nitromine provided access to the primary
imine 11. Oxidation from the endo face with mCPBA then afforded the N-H oxaziridine
12 as a 60:40 mixture of diastereomers at nitrogen. Derivatization
studies were used to confirm the facial selectivity of the oxidation
and the identity of the diastereomers. Unlike many N-H oxaziridines, compound 12 could
be isolated in pure
form and stored up to 6 months at 5 °C without noticeable decomposition
(Scheme 3).
Scheme 3
Preparation of Chiral N–H Oxaziridine
2.3
N-Acyl- and N-(Alkoxycarbonyl)oxaziridines
N-Acyloxaziridines
are typically generated by acylation of the corresponding N-H oxaziridines (eq 3).
33
The application of these compounds to organic
synthesis has been limited; however, Jennings et al. used this class
of oxaziridines to probe substituent effects on nitrogen inversion.
34
Although N-alkyloxaziridines
exhibit a high barrier of inversion at the oxaziridine nitrogen (25–32
kcal/mol), the presence of an N-acyl group significantly
lowers this barrier to 10.3 kcal/mol for oxaziridine 13. This large effect is due
to strong stabilizing π-conjugation
in the transition state for nitrogen inversion and is a general phenomenon
for N-substituents capable of conjugation; N-(alkoxycarbonyl)-, N-sulfonyl-, and N-phosphinoyloxaziridines
also have lower barriers of inversion
relative to N-alkyloxaziridines.
3
The preparation of N-(alkoxycarbonyl)oxaziridines
can also be achieved starting from
the corresponding imines. In the case of the N-Boc-oxaziridines,
the most thoroughly investigated N-(alkoxycarbonyl)oxaziridines,
the synthesis proceeds from an aza-Wittig reaction of the corresponding
aldehyde to give an N-Boc imine. This imine can then
be oxidized with basic buffered oxone, mCPBA, or
the anhydrous mCPBA lithium salt. The related N-Moc- and N-Fmoc-oxaziridines are also
prepared via oxidation of the corresponding imines, which can be prepared
by acylation of N-silylimine 17 using
the appropriate chloroformate (Scheme 4).
35
Scheme 4
Synthesis of N-Carbamoyloxaziridines
Ketone-derived N-Boc-oxaziridines have also been
reported.
36
Utilizing the aza-Wittig reagent 15, diethyl ketomalonate can be converted to oxaziridine
20 in the standard two-step sequence. Additionally, the Armstrong
group reported a route to the key aza-Wittig reagent 15 that avoids the use of the
potentially hazardous Boc azide (Scheme 5).
37
Scheme 5
Synthesis of Armstrong’s N-Boc-oxaziridine
The barrier of inversion for N-Boc-oxaziridines
has been calculated to be ∼18 kcal mol–1 at
27 °C. In solution, N-(alkoxycarbonyl)oxaziridines
exist as a mixture of interconverting trans and cis conformers (∼80–93%
trans depending on structure) with a conformer half-life of ∼3
s at 20 °C.
35c
Compared to the aforementioned N-alkyloxaziridines, this barrier is lower and the
difference
in energy is also generally rationalized by assuming that conjugation
of the planar nitrogen with the alkoxycarbonyl group lowers the energy
barrier of the transition state.
2.4
N-Sulfonyloxaziridines
Soon after Davis et al.
first described their synthesis in 1977,
38
N-sulfonyloxaziridines quickly
became the most extensively utilized class of oxaziridine in organic
synthesis because of their stability, ease of synthesis, and superior
oxidizing ability compared to N-alkyloxaziridines.
Now commonly referred to as “Davis’ oxaziridines”, N-sulfonyloxaziridines are generally
prepared by oxidation
of the corresponding N-sulfonyl imines, which in
turn can be prepared by condensation of sulfonamides (RSO2NH2) with aromatic aldehydes
using either Brønsted
39
or Lewis
40
acids.
While the earliest reports described the oxidation of N-sulfonyl imines with mCPBA
in the presence of a
phase transfer catalyst,
39
the use of buffered
potassium peroxymonosulfate (Oxone) provides a less expensive and
more practical alternative.
41
This approach
has also been applied to the synthesis Davis’ oxaziridine on
a large scale, which can provide over 100 g of the resulting oxaziridine
in two steps from the corresponding aldehyde.
42
More challenging imine oxidations have also been reported using
KOH/mCPBA
43
or peroxyimidate-mediated
oxidations that utilize H2O2 as the stoichiometric
oxidant.
17b
For example, the oxidation
of polystyrene-supported N-sulfonyl aldimines required
the use of KOH/m-CPBA, which produces solid-phase
oxidants with reactivity comparable to that of soluble small-molecule
oxaziridines of analogous structure.
44
Finally,
while Davis’ oxaziridines are most commonly derived from aldimines,
several oxaziridines derived from ketimines have proven to be quite
important reagents for organic synthesis (Scheme 6).
45,46
Scheme 6
Syntheses of N-Sulfonyloxaziridines
In general, N-sulfonyloxaziridines are
stable
crystalline compounds that exist in a trans configuration. In order
to determine whether this selectivity was the result of kinetic or
thermodynamic product control, Jennings prepared a series of 3,3-disubstituted-2-sulfonyloxaziridines
and measured the rate of nitrogen inversion by variable temperature
NMR.
47
The barrier of inversion (ΔG
‡ ∼ 20 kcal/mol) measured for N-sulfonyloxaziridines is significantly lower than those
of their N-alkyl counterparts (ΔG
⧧ ∼ 32 kcal/mol),
22
which suggests that N-sulfonyloxaziridines can
undergo spontaneous stereomutation at ambient temperature and that
the high trans diastereoselectivity observed in the preparation of
these oxaziridines is under thermodynamic control.
The earliest
attempts to prepare optically active N-sulfonyloxaziridines
relied on the use of a chiral camphor-based
peracid;
48
however, this approach suffers
from low selectivity, and repeated fractional recrystallizations are
required to achieve high optical purity using this protocol. The first
synthetically useful approach to chiral N-sulfonyloxaziridines
was based on the synthesis of camphor sulfonic acid derived imine 30, which can be
selectively oxidized with oxone to give oxaziridine 31.
49
The oxidation can only take
place from the endo face of the C=N double bond due to the
steric blocking of the exo-face, which results in a single oxaziridine
isomer (Scheme 7). Davis and Chen have reviewed
the use of this reagent in a number of asymmetric oxygen transfer
reactions.
12b
An optically active N-sulfamyloxaziridine has also been reported.
50
Scheme 7
Synthesis of Davis’ Chiral Camphor-Derived
Oxaziridine 31
Recently, several successful efforts to produce highly
enantioenriched N-sulfonyloxaziridines via asymmetric
catalysis have been
reported in rapid succession (Scheme 8). The
first catalytic enantioselective synthesis of oxaziridines was reported
by Jørgensen and co-workers in 2011, which described the oxidation
of N-tosyl imines utilizing a cinchona-alkaloid-based
bifunctional phase-transfer catalyst.
51
The following year, a sulfonyl-directed oxidation of N-sulfonyl imines catalyzed by
a chiral hafnium complex was reported
by Yamamoto and co-workers.
52
Finally,
Ooi and co-workers reported an asymmetric Payne-type oxidation of N-sulfonyl imines
using chiral base 36 and
trichloroacetonitrile.
53
Scheme 8
Catalytic Enantioselective
Routes to Chiral Oxaziridines
2.5
N-Phosphinoyloxaziridines
Oxaziridines bearing N-phosphinoyl groups were
first synthesized by Boyd et al.
54
This
class of oxaziridine is typically accessed via reaction of an aryl
oxime with chlorodiphenylphosphine, followed by oxidation of the rearranged N-phosphinoyl
imine with mCPBA (Scheme 9). These oxaziridines are stable compounds that
have a low barrier to nitrogen inversion (∼13 kcal/mol) and
exist in the trans configuration. This barrier of inversion is lower
than for the related N-sulfonyloxaziridines, which
has been rationalized as the effect of a stronger conjugative interaction
between nitrogen and phosphorus than between nitrogen and sulfur in
the transition state for epimerization.
55,56
Scheme 9
Synthesis
of N-Phosphinoyloxaziridines
Jennings et al. also synthesized optically active N-phosphinoyloxaziridines with a
stereogenic phosphorus
center.
57
Due to the potential of chlorophosphorus
reagents
to racemize by chloride exchange, the corresponding chiral N-phosphinoyl imines are
prepared from the optically active
phosphinic amides. For example, condensation of amide 40 and aryl aldehyde 41 proceeds
cleanly in the presence
of titanium(IV) chloride and triethylamine, and oxidation of the resulting N-phosphinoyl
imine in situ with mCPBA/KF
provides oxaziridine 42 as a 2.6:1 mixture of diastereomers
(eq 4). Selective recrystallization can be used
to access highly enantioenriched, diastereomerically pure oxaziridines.
4
2.6
N-Silyloxaziridines
Oxaziridines
bearing an N-silyl group have been
reported by Vidal and co-workers.
58
Due
to the sensitivity of most N-silylamines to moisture
and acid, only the tert-butyldiphenylsilyl (TBDPS)
derivative has been successfully synthesized. The route involves silylation
of benzylamine 43 to give the N-TBDPS
amine 44, which is oxidized to the imine in a two-step
sequence involving chlorination of the amine with tert-butyl hypochlorite and elimination
with DBU. Oxidation with mCPBA/KOH affords the N-silyloxaziridine 46 (Scheme 10).
A more direct approach
via derivatization of the corresponding N-H oxaziridine
was also investigated; however, the instability of the intermediates
made this approach unviable.
Scheme 10
Synthesis of N-Silyloxaziridine
3
Reactivity
of Oxaziridines
3.1
Oxygen Atom Transfer
Oxaziridines
have been most commonly utilized in synthesis as electrophilic, aprotic
sources of oxygen. In particular, N-sulfonyloxaziridines
have been widely investigated for their ability to transfer oxygen
to a range of nucleophiles. Oxygen atom transfer to sulfur,
59
phosphorus,
60
selenium,
61
nitrogen,
62
and carbon
nucleophiles
63
produces the oxygenated
products with the corresponding imine as a stoichiometric byproduct.
Over the past 20 years, the majority of research on the chemistry
of N-sulfonyloxaziridines has focused on the development
of new oxaziridines with a broader synthetic scope, asymmetric induction
in the oxaziridine-mediated oxidation of prochiral substrates, and
the application of these reagents in total synthesis.
3.1.1
Olefin Epoxidation
At elevated
temperatures, Davis’ oxaziridines can be utilized to synthesize
epoxides from alkenes.
64
Experimentally,
the transition state for the transfer of oxygen from N-sulfonyloxaziridines to alkenes
has been investigated using the
endocyclic restriction test.
65
By evaluating
a number of substrates containing an oxaziridine and an alkene, Beak
and co-workers concluded that the transition state of oxygen transfer
from an N-sulfonyloxaziridine to a corresponding
nucleophile is one in which N–O bond cleavage is more advanced
than C–O bond cleavage (Figure 2, 47). Houk et al. also performed computational studies
that
probe the transfer of oxygen from oxaziridines to alkenes. These calculations
similarly indicate a concerted, asynchronous process; advanced cleavage
of the N–O bond is accompanied by significant buildup of partial
negative charge at nitrogen.
66
Thus, to
a first approximation, oxaziridines can be considered electrophilic
oxidants, and factors that stabilize the incipient negative charge
at nitrogen are expected to increase the reactivity of oxaziridines.
Figure 2
Asynchronous
transition state for oxygen atom transfer reactions
of N-sulfonyloxaziridines.
Indeed, substitution of oxaziridines with electron-withdrawing
groups significantly increases their reactivity toward oxygen transfer.
For example, epoxidation of monosubstituted olefins fails to proceed
with N-(benzenesulfonyl)oxaziridine 23, even at elevated temperatures.
64
Upon
using a more electrophilic perfluoroalkyloxaziridine 5, however, 1-octene is efficiently
epoxidized in less than 1 h at
−40 °C (Figure 3).
67
Figure 3
Electronic influence on oxaziridine reactivity.
Quaternized oxaziridinium salts, first investigated
by Lusinchi
and co-workers,
68
have also been explored
in oxygen transfer reactions to alkenes.
69
Consistent with the general trend that electron-deficient oxaziridines
tend to be more powerful oxygen atom-transfer reagents, these positively
charged oxaziridinium salts efficiently epoxidize alkenes at ambient
temperatures. These reagents can be generated catalytically from the
corresponding iminium salt in the presence of a stoichiometric oxidant,
typically Oxone. Chiral iminium salts have thus been used in catalytic
asymmetric epoxidation reactions with moderate to excellent enantioselectivities
(eq 7).
70
7
The Frontier group reported an elegant cascade reaction initiated
by oxaziridine-mediated oxidation of an allene (eq 8). Vinyl allene 53 smoothly reacts
with N-sulfonyloxaziridine 27, and the resulting
putative dienyl cation is poised to undergo a subsequent Nazarov cyclization.
71
When more reactive oxidants such as dimethyldioxirane
are used, the reaction proceeds with lower selectivity.
8
3.1.2
Sulfur Oxidation
The ability of N-sulfonyloxaziridines to oxidize sulfides to sulfoxides
has been widely explored.
72
In general,
sulfides can be quantitatively oxidized to sulfoxides in minutes with
minimal overoxidation to the corresponding sulfone. Catalytic systems
in which Oxone oxidation of a substoichiometric amount of sulfonimine
to generate a reactive oxaziridine in situ have also been disclosed.
Mechanistically, these atom transfer reactions are considered to proceed
via an SN2 attack on the oxaziridine oxygen with concomitant
displacement of the imine as a leaving group.
73
The asymmetric synthesis of chiral sulfoxides with optically
active oxaziridines has been an area of considerable continuing interest.
74
Early investigations involving chiral N-sulfamyl-,
50
N-sulfonyl-,
75
and N-phosphinoyloxaziridines
57
demonstrated the feasibility of chirality transfer
from oxaziridines to a wide range of sulfoxides. Despite generally
rather modest and substrate-dependent levels of enantioselectivity,
these reactions can be convenient and readily scalable, and in certain
cases the stereoselectivities have been optimized to quite high levels.
For example, a kilogram-scale synthesis of the proton pump inhibitor
rabeprazole (57) has been reported, in which the key
step involved sulfoxidation of 56 mediated by camphor-derived
oxaziridine 31 (Scheme 11).
74a
Scheme 11
Synthesis of Rabeprazole Using Camphor-Derived
Oxaziridine 31
A method for catalytic sulfoxidation was reported by Page
and co-workers.
This system utilizes a chiral saccharin-based imine as the catalyst
and hydrogen peroxide as the stoichiometric oxidant.
76
The authors were able to confirm catalytic turnover in
sulfoxidation reactions of the chiral imine, but enantiomeric excesses
were low. Additionally, the use of stoichiometric oxaziridine in these
reactions led to different levels of enantioselectivity, thus indicating
that different species may be contributing to the selectivity observed
in the catalytic system (eq 9).
9
The use of exogenous additives for the asymmetric oxidation
of
sulfides with chiral N-alkyloxaziridines has also
been investigated. While N-(perfluoroalkyl)oxaziridine
analogues rapidly oxidize sulfides to the corresponding sulfoxide
or sulfone depending on the equivalents of oxidant,
77
normal N-alkyloxaziridines are generally
insufficiently reactive to participate in oxygen transfer unless forcing
high-pressure conditions are used.
78
Bohé
et al. observed that the addition of exogeneous acid additives promotes
sulfide oxidation by oxaziridine 63 in modest enantioselectivity
(eq 10).
79
The rate
acceleration is proposed to be a result of protonation of the basic
nitrogen to give the corresponding oxaziridinium in situ.
10
Fontecave and co-workers also reported Lewis acid mediated
activation
of chiral N-alkyloxaziridines using ZnCl2.
80
Oxidation of 65 with
(S)-1-phenylethylamine-derived 3-pyridyloxaziridine 64 resulted in the formation of
sulfoxide 66 with
modest enantioselectivity. The necessity of a heteroaromatic substitutent
on the oxaziridine led the authors to propose that Lewis acid activated
intermediate 67 is the active oxidizing species. Coordination
of the Lewis acid to the nitrogen atom of the oxaziridine is believed
to increase the electron deficiency of the oxygen atom, thus enhancing
its electrophilicity (Scheme 12).
Scheme 12
Lewis
Acid Activation of Chiral N-Alkyloxaziridines
The ability of N-sulfonyloxaziridines to oxidize
thiols has also been investigated. The reaction between thiols and N-sulfonyloxaziridines
typically results in the production
of sulfinic acids. Davis and Billmers demonstrated that sulfenic acids
are intermediates in this process
81
and
that the rate of sulfenic acid oxidation outcompetes thiol oxidation
even when a large excess of thiol is used. Perrio and co-workers subsequently
investigated chemoselective thiol functionalizations with pinacolone-derived N-sulfonyloxaziridine
27. The oxidation of
aromatic thiols to sulfoxides has been reported in a three-step, one-pot
procedure involving deprotonation of the thiol, oxidation with oxaziridine 27, and
trapping of the sulfenate anion with an alkyl halide
(eq 11).
82,83
Notably, this sequence
proceeds without disulfide formation or O-alkylation.
11
The scope of oxidation reactions with oxaziridine 27 has also been extended beyond
aromatic thiols. Dithioester-based
enethiolates can be chemoselectively oxidized with oxaziridine 27 to afford the ketene
dithioacetal S-oxide
in good yield (eq 12).
46a
Additionally, the base-induced fragmentation of 4-substituted 1,2,3-thiadiazoles
produces acetylenic thiolates that can be oxidized and alkylated to
provide 1-alkynyl sulfenates (eq 13).
46b
Aliphatic thiols have also been converted to
sulfones using 2 equiv of the oxidant.
84
12
13
The ability of oxaziridine 27 to act as a weak
oxidant
has also been exploited for the selective oxidation of sulfur-containing
ligands. Alves de Sousa and Artaud demonstrated that careful control
of reagent stoichiometry can allow the generation of mixed sulfonate/thioether
and mixed sulfonate/sulfoxide compounds that were investigated for
their ability to bind metal cations.
85
Additionally,
Kovacs and co-workers utilized a selective oxidation of an iron thiolate
complex to investigate how the addition of an oxygen atom affected
the properties of Fe–nitrile hydratase analogues.
86
3.1.3
Amine Oxidation
A well-established
mode of reactivity for Davis’ oxaziridines is the transfer
of oxygen to secondary amines to yield hydroxylamines.
61
Rapoport and co-workers applied this process
toward the enantioselective formal synthesis of (+)-FR900482.
87
In the route, intermediate 74 was
oxidized with Davis’ oxaziridine and subsequently protected
to give acetoxyamine 75 in good yield. Notably, the use
of more common oxidants like mCPBA and MMPP led to
lower yields, which highlights the ability of N-sulfonyloxaziridines
to act as a mild aprotic, electrophilic source of oxygen (eq 14).
14
3.1.4
Enamine Oxidation
Davis also investigated
the oxidation of enamines by N-sulfonyloxaziridines.
Disubstituted and trisubstituted enamines are rapidly oxidized to
α-amino and α-hydroxy ketones, respectively.
88
A mechanism involving initial oxidation to an
α-amino epoxide was proposed to account for the product distributions.
The oxaziridine-mediated oxidation of indoles has proven to be particularly
useful in the synthesis of a variety of structurally complex alkaloids.
For example, the Snider group exploited an oxaziridine-mediated indole
oxidation as a key step of their synthesis of asperlicin and asperlicin
C (Scheme 13).
89
The advanced indole 76 was oxidized with oxaziridine 77 in methanol to give a 71%
yield of an 11:1 mixture favoring
the α-alcohol after ring-opening of the epoxide. Directed reduction
of the C-2 position, reoxidation of the dihydroquinazolinone, and
hydrogenolysis of the Cbz group then gave the natural product 79. Similar recent applications
of indole oxidation in alkaloid
synthesis include the Snider syntheses of the fumiquinazoline natural
products
90
and Williams’ synthesis
of versicolamide B.
91
Scheme 13
Oxaziridine-Mediated
Indole Oxidation in the Synthesis of Asperlicin
In 2011, Movassaghi and co-workers demonstrated
the utility of
camphor-derived (+)-((8,8-dichlorocamphoryl)sulfonyl)oxaziridine in
their synthesis of the trigonoliimine natural product family.
92
Oxidation of bistryptamine 80 with
oxaziridine 81 provided hydroxyindolenines 82a and 82b with excellent yield and enantioselectivity.
These isomeric hydroxyindolenines served as a useful branching point
to access each member of the trigonoliimine family by judicious choice
of synthetic sequence (Scheme 14).
Scheme 14
Asymmetric
Indole Oxidation in the Synthesis of Trigonoliimine Natural
Products
3.1.5
Enolate
Oxidations
The oxidation
of enolates to α-hydroxycarbonyl compounds is arguably the most
widely utilized reaction of oxaziridines. The products of these reactions
are valuable intermediates in organic synthesis and key structural
motifs in many biologically active natural products; several recently
completed targets whose syntheses feature oxazirdine-mediated enolate
oxidations are featured in Figure 4.
93
Prior reviews have detailed early approaches
to generating these bonds with facial selectivity utilizing both chiral
auxiliaries approaches
94
and optically
active oxaziridines.
95
Much of the contemporary
interest in this area has focused on catalytic asymmetric α-oxidations
of carbonyl compounds using N-sulfonyloxaziridines
as terminal oxidants.
Figure 4
Target molecules synthesized using oxaziridine-mediated
α-hydroxylation.
Mezzetti, Togni, and co-workers described an asymmetric hydroxylation
of β-keto esters catalyzed by a chiral titanium(IV) TADDOLate
complex (eq 15).
96
The authors suggest that coordination of the Lewis acid catalyst
to the β-keto ester substrate results in the formation of a
chiral titanium enolate. This enolate then reacts with N-sulfonyloxaziridine 91 to
give α-hydroxylated
products with up to 94% ee; however, the selectivity is generally
modest if the ester substituent is less sterically demanding than
a tert-butyl group. A copper(I)-catalyzed asymmetric
α-hydroxylation of β-keto esters has also been reported
utilizing a phosphine-Schiff base ligand, but observed enantioselectivities
were generally somewhat modest.
97
15
Conceptually similar Lewis acid-catalyzed enantioselective
α-hydroxylations
of other classes of enolates have also been reported. Shibata, Toru,
and co-workers recently reported that zinc(II) DBFOX complex 96 catalyzes the highly
enantioselective hydroxylation of
3-aryl-2-oxindoles, which they propose proceeds by a similar mechanism
involving Lewis acid-promoted enolization of the oxindole substrate
(eq 16).
98
Additionally,
Shibasaki and co-workers demonstrated a highly stereoselective α-hydroxylation
of α-substituted α-alkoxycarbonyl amides using a praseodynium/amide 99-based catalyst
system and Davis’ oxaziridine 23 (eq 17).
99
16
17
In addition to Lewis acid-mediated approaches to catalytic enantioselective
α-hydroxylation, there have been a number of highly enantioselective
organocatalytic routes to α-hydroxylated carbonyl compounds
involving oxaziridine as oxidants.
100
Utilizing
the l-tartrate-derived chiral guanidine 102,
Zou et al. developed the α-hydroxylation of β-keto ester
and β-dicarbonyl substrates with exceptional yields and enantioselectivities
(eq 18). N-Tosyloxaziridine 33 proved to be much more selective than the other sources
of electrophilic oxygen investigated.
18
3.1.6
C–H Functionalization
Oxaziridines
have also been used to achieve the selective oxyfunctionalization
of C–H bonds. Due to the oxidizing power required to achieve
this type of transformation, most of the early reports of this reactivity
involved the use of highly electron-deficient perfluorinated oxaziridines
in order to convert alkane C–H bonds to alcohols under ambient
conditions.
101
The use of perfluorinated
oxaziridines in C–H functionalization reactions has been the
subject of a previous review
12c
and will
not be covered here.
The Du Bois group developed a catalytic
system for C–H hydroxylation utilizing a fluorine-containing
benzoxathiazine-based oxaziridine.
102
The
authors used DFT calculations to design the highly electron-deficient
oxaziridine 106, which they predicted would be a viable
oxidant for C–H functionalization. This reagent can be prepared
in a four-step sequence in gram quantities from the corresponding
aryl bromide 103 (Scheme 15) and
was shown to be a viable reagent for the oxidation of C–H bonds.
Scheme 15
Du Bois’ Fluorinated Benzoxathiazine-Based Oxaziridine
In addition to using oxaziridine 106 as a stoichiometric
reagent for C–H functionalization, Du Bois and co-workers demonstrated
that the imine 105 can also be used in catalytic quantities
in the presence of urea–hydrogen peroxide (UHP) as the stoichiometric
oxidant to generate oxaziridine 106 in situ (eq 19). Their reaction design involved
two cocatalytic
components. First, catalytic diselenide 109 [Ar = 3,5-bis(trifluoromethyl)phenyl]
reacts with stoichiometric H2O2 to produce perselenimic
acid in situ. This oxidant then reacts with benzoxathiazine-derived
imine 105 to produce the active oxaziridine. Under these
conditions, a number of unactivated C–H bonds could be smoothly
oxidized. In 2009, a redesigned benzoxathiazine-based oxaziridine
was reported for selective tertiary C–H bond oxidation under
aqueous acetic acid/H2O2 conditions.
103
19
Recently, the Aubé group reported the
Cu(I)-catalyzed formal
insertion of the oxygen atom of an oxaziridine into activated C–H
bonds (Scheme 16).
104
The authors proposed that Cu(I)-promoted homolysis of N-cyclohexyloxaziridine 110
resulted in Cu(II)-stabilized
radical/anion pair 112. Subsequent 1,5-hydrogen atom
abstraction by the reactive nitrogen-centered radical affords allylic
radical 113, which can then undergo radical recombination
with the copper(II) alkoxide to regenerate the Cu(I) catalyst and
liberate 2-aminotetrohydrofuran 114. This intermediate
undergoes hydrolysis to produce the observed keto alcohol product 111. Benzylic and
propargylic C–H bonds could also
be oxidized in modest to good yield.
Scheme 16
Cu(I)-Catalyzed
C–H Oxidation
Shi and co-workers reported an unusual example of a C–H
functionalization reaction in which an oxaziridine transfers a carbon-centered
functional group (eq 20).
105
This reaction presumably involves the metallocycle that
arises from Pd(II)-catalyzed C–H activation of 2-phenylpyridine,
which then reacts with oxaziridine 116 in a novel alkoxycarbonylation
reaction to afford ester 117 in high yield. While the
mechanistic details of this reaction await further interrogation,
this is an unusual example of a reaction in which an oxaziridine oxidant
participates in a reaction by transferring a moiety other than oxygen
or nitrogen.
20
3.2
Nitrogen Atom Transfer
Oxaziridines
can act as sources of electrophilic nitrogen when the N-substituent is small. For
many years, the reagents of choice for
these transformations were N-H oxaziridines, particularly
1-oxa-2-azaspiro[2.5]octane 7. This work was largely
pioneered by Schmitz and co-workers, and an account detailing many
of the synthetic applications of oxaziridines in this class has been
compiled.
12d
Given the high reactivity
of these reagents, however, the broader application of Schmitz-type
oxaziridines in synthesis has been somewhat limited due to the requirement
that they should be prepared in situ. This has led to continued interest
in designing oxaziridine reagents that can act as electrophilic sources
of nitrogen with improved practicality.
3.2.1
Amination
of Nitrogen Nucleophiles
Collet and co-workers designed N-carbamoyloxaziridine 16 to address the challenges
outlined above (Scheme 17). In addition to
being an isolable and stable
crystalline solid, the ability of oxaziridine 16 to transfer
nitrogen in protected form is highly attractive. Due to the Collet
group’s interest in hydrazido peptides, the authors investigated
the amination of various amines to produce N-Boc-hydrazides.
35
Both secondary (eq 21) and primary amines (eq
22) react to give products in good yield; however, competitive Schiff
base formation with the 4-cyanobenzaldehyde byproduct can be problematic
and leads to reduced yields with some primary amine substrates. Nevertheless,
a number of research groups have utilized these N-Boc-hydrazines as building blocks
for molecules of biological interest.
106
Scheme 17
Amination of Amines with Oxaziridine
Armstrong et al. attempted
to address the problematic side reactions
of the aldehyde byproduct generated from nitrogen transfer reactions
with oxaziridine 20.
37
Utilizing
the diethyl ketomalonate-derived N-Boc-oxaziridine 20, a number of primary amines
were aminated to N-Boc-hydrazides (123) in good yield without a significant
amount of deleterious imine formation (eq 23). The authors also applied this methodology
to a one-pot synthesis
of 1,3,5-trisubstituted pyrazoles.
23
Vidal and co-workers
also reported an intriguing amination of amines
with N-silyloxaziridine 46. Primary
and secondary amines react to give the corresponding hydrazine in
moderate to good yield (eq 24).
58
Unlike other N-substituted aminating oxaziridines,
however, the N-silyl variant does not transfer the
nitrogen-protecting group to the observed products. The authors propose
that the reaction proceeds via 127, an aza-analogue of
the β-hydroxysilane intermediate in Peterson olefination, to
account for the observed hydrazine (Scheme 18).
24
Scheme 18
Rationale for Divergent Reactivity of N-Silyloxaziridine 46
3.2.2
Amination of Carbon Nucleophiles
N-(Alkoxycarbonyl)oxaziridines can also react with
carbon nucleophiles. Oxaziridine 16 reacts with various
enolates to give electrophilic amination products, albeit in modest
yield (Scheme 19).
35
Competitive aldol condensation between the released 4-cyanobenzaldehyde
and the enolate results in a loss of overall reaction efficiency.
Amide and ester enolates also react in similar yields; however, silyl
enol ethers are epoxidized to give the α-hydroxy ketone product.
Enders exploited the nitrogen atom transfer reactivity of N-Boc-oxaziridines in the
asymmetric synthesis of α-amino
ketones using chiral α′-silyl ketones.
107
Scheme 19
Amination of Enolates with N-Boc-oxaziridine 16
Ghoraf and Vidal
demonstrated that N-Boc-oxaziridines
also transfer nitrogen to organometallic species. After surveying
different classes of organozinc reagents, the authors found that diorganozinc
compounds are optimal for reactions with oxaziridine 16 to give a variety of N-Boc-protected
primary amines
(eq 25).
108
To rationalize
the selectivity of nitrogen transfer over oxygen transfer, the authors
propose that the oxygen atom of oxaziridine 16 acts as
a Lewis base to form a zincate complex. This activates attack of the
electrophilic nitrogen by the organozinc compound, which leads to
observed product after acidic workup.
25
3.2.3
Amination of Sulfides
Collet and
co-workers have also investigated the use of oxaziridine 16 for the amination of sulfides;
however, competitive oxygen transfer
leads to complex product mixtures and low yields.
35
Armstrong and Cooke demonstrated that higher levels of
selective amidation can be achieved using the diethyl ketomalonate-derived N-Boc-oxaziridine
20 (eq 26).
36
While the reasons for the higher
chemoselectivity are unclear, it was hypothesized that steric interactions
between the N-alkoxycarbonyl group and the ester
substituents might disfavor oxygen transfer.
26
The Armstrong group also developed
a clever application of this sulfide amination using allylic
36
and propargylic
109
sulfides. Upon amidation of the sulfur moiety, the intermediate
sulfimides undergo rapid [2,3]-sigmatropic rearrangement to yield
allylic and allenic amines, respectively. When applied to chiral allylic
sulfides, the reactions proceed with complete transfer of chirality.
110
Desulfurization of these compounds with triethyl
phosphite results in (E)-vinylglycine derivatives.
Due to the mildness of the reaction conditions, a one-pot amination/rearrangement/N–S
bond cleavage sequence can be performed in good overall yield (eq 27).
111
27
3.2.4
Amination of Alkoxides
Both N-H and N-Boc-oxaziridines have been applied
to the amination of alkoxides to give alkoxyamines. Choong and Elmann
demonstrated that 3,3-di-tert-butyloxaziridine 140 can be used for the amination of
a variety of primary
and secondary alcohols in good yield (eq 28).
112
Unlike the highly reactive, base-sensitive
cyclohexanespiro-3′-oxaziridine 7, the increased
steric hindrance of oxaziridine 140 adds significant
stability. Oxaziridine 140 can be isolated in pure form
and stored at room temperature for months without decomposition. Additionally,
the steric hindrance of the 2,2,4,4-tetramethyl-3-pentanone byproduct
prevents condensation with the desired alkoxyamine product. As one
might expect, this steric encumbrance does limit substrate scope;
tertiary alcohol products were isolated in low yield.
28
Foot and Knight also developed a mild
method for the electrophilic amination of alkoxides utilizing chloral-based
oxaziridine 143 (eq 29).
113
Primary, secondary, tertiary, allylic, propargylic,
and phenolic alkoxides can be aminated in moderate to excellent yields.
29
3.2.5
C–H Amination
Few examples
of formal nitrogen atom transfer reactions from N-sulfonyloxaziridines have been documented.
The Yoon laboratory demonstrated
that treatment of oxaziridine 145 with CuCl2 in the presence of LiCl results in the
regioselective net insertion
of the oxaziridine nitrogen into an sp3-hybridized C–H
bond with exclusive formation of a six-membered ring (Scheme 20).
114
No trace of insertion
into the other possible alkane position was observed. Indeed, the
regioselectivity for functionalization of the δ position is
high, even when the reacting methylene position is unactivated (i.e.,
when Ph = alkyl). The aminal intermediates are amenable to further
synthetic manipulations (e.g., to 147, 148), which enables the rapid synthesis of
piperidine-containing structures
that are common features of a variety of potent bioactive alkaloids.
Scheme 20
Copper Catalyzed C–H Amination with N-Sulfonyloxaziridines
3.3
Transition-Metal-Promoted
Rearrangements
Oxaziridines participate in a remarkably broad
variety of rearrangement
reactions when exposed to exogenous chemical and photochemical stimuli.
Acid-mediated rearrangements to hydroxylamines,
115
base-catalyzed eliminations,
116
thermal rearrangements to nitrones,
117
and photochemical isomerizations
118
have
all been extensively studied and reviewed.
119
In addition, the Aubé group elegantly demonstrated the synthetic
utility of photochemical isomerizations of oxaziridines in their synthesis
of the yohimbine alkaloids.
120
Recent
investigations of reactions involving rearrangements of oxaziridines
have focused on activation by redox-active transition metals. The
ability of oxaziridine rearrangements to be initiated by single-electron
transfer is consistent with many of their other properties. For example,
theoretical calculations probing the epoxidation of ethylene by oxaziridine
indicate a substantial buildup of radical spin density at the reacting
carbon of the olefin and on the nitrogen of the oxaziridine.
66
The concerted atom transfer reactions of oxaziridines
can therefore be considered to have significant diradical character.
The first report of transition-metal-catalyzed rearrangement of
oxaziridines to amides dates to the earliest papers detailing the
synthesis and isolation of oxaziridines. In 1957, Emmons reported
that treatment of oxaziridine 2 with catalytic ammonium
iron(II) sulfate in water generated N-tert-butylbenzamide 149 in 68% yield (Scheme
21, eq 30).
10
When ketone derived
oxaziridines are subjected to the reaction conditions, radical cleavage
products resulting from β-scission processes predominate. For
example, treatment of triethyloxaziridine 150 with iron
sulfate leads to diethyl ketone (50%), N-ethylpropionamide
(32%), ammonia (55%), and a mixture of butane, ethane, and ethylene
gases (Scheme 21, eq 31).
Scheme 21
Iron-Catalyzed Rearrangement
of N-Alkyloxaziridines
Minisci and co-workers investigated the mechanism for
the transition-metal-catalyzed
rearrangement of oxaziridines to amides.
121
They suggested that formation of the more stable nitrogen-centered
radical rather than an oxygen-centered radical was the favored pathway
for decomposition of the oxaziridine. Thus, one-electron reduction
of an oxaziridine by a redox-active transition metal generates a nitrogen-centered
radical, which can either undergo 1,2-hydrogen atom migration with
a chain-propagating one-electron oxidation by another equivalent of
oxaziridine or undergo radical cleavage (Scheme 22).
Scheme 22
Proposed Mechanism of Iron-Catalyzed Rearrangement
to Amides
Several groups have
recognized that the ability to oxidize an imine
to an amide via an intermediate oxaziridine is a synthetically valuable
process. Black et al.
122
demonstrated that
stoichiometric iron(II) sulfate can effect the rearrangement of a
series of oxaziridines such as 153 to the corresponding
pyrrolin-2-ones 154 (eq 32). In
this case, amide formation proceeds by loss of a stable tert-butyl radical via β-scission
of the nitrogen-centered radical.
This methodology was also extended to formation of 3-alkylidenepyrrolin-2-ones
(156) by rearrangement of the corresponding oxaziridines
(155) (eq 33). Although the authors
reported that the reaction proceeds with catalytic iron(II) sulfate,
stoichiometric iron(II) salts led to shorter reaction times and fewer
byproducts. Presumably, since the rearrangement can proceed under
catalytic conditions, the tert-butyl radical can
act as a radical initiator for rearrangement of the oxaziridine to
the amide.
32
33
More recent investigations into the transition-metal-catalyzed
rearrangement of oxaziridines to amides have sought to improve the
practicality and efficiency of the transformation. In 1994, Suda
123
reported a manganese-catalyzed rearrangement
of N-phenylspirooxaziridine 157 to lactam 158 through a ring expansion. The reaction
proceeds in high
yield using 2 mol % of a manganese(III) tetraphenylporphyrin catalyst
(eq 34). Importantly, a range of lactam ring
sizes could be generated in high yield using this catalytic method
simply by changing the nature of the starting oxaziridine. Although
the authors suggest that this transformation may proceed by an ionic
and not electron transfer mechanism, the mechanism was not studied
in detail. In a similar report, Eisenstein and co-workers
124
reported that cyclic, 3-arlyoxaziridines such
as 159 could be converted to the corresponding amide 160 using the same manganese
catalyst, albeit under more forcing
reaction conditions (eq 35).
34
35
Transition-metal catalyzed rearrangements of oxaziridines are not
limited to the formation of amides. Catalytic reactions that take
advantage of the formation of a nitrogen-centered radical for intramolecular
cyclizations and fragmentations have also been developed. Aubé
and co-workers studied intramolecular radical cyclizations with oxaziridines
and found that product distributions are heavily dependent on oxaziridine
substitution.
125
For instance, each diastereomer
of alkene-bearing oxaziridine 161 forms a different product
when treated with catalytic amounts of a copper(I) salt (Scheme 21).
126
The authors proposed
that treatment of diastereomer 161a with 5 mol % of a
copper(I) catalyst generates the nitrogen-centered radical, which
can undergo intramolecular cyclization with the olefin to generate
primary radical 163 (Scheme 23a). The carbon-centered radical in 163 can then attack
the aromatic ring, which is transferred, generating a stabilized radical
α to the amine. After regeneration of the copper(I) salt and
loss of acetaldehyde, pyrroline 167 is formed. For diastereomer 161b, however, the
authors suggest that radical 168 is incapable of reacting with the aryl ring due to
geometrical constraints.
As a result, aziridine 170 is the favored product (Scheme 23b).
Scheme 23
Intramolecular Radical Amine Cyclizations
with Oxaziridines
Aubé et al. also studied single-electron transfer
reactions
of oxaziridines other than nitrogen radical cyclizations. For example,
oxaziridines bearing substituents β to the nitrogen that readily
form a stabilized radical (e.g., 171) can undergo β-scission
to generate a carbon-centered radical and the corresponding amide 173 (Scheme 24a).
127
Aubé and co-workers also recognized that the carbon
radical generated by β-scission from the nitrogen radical could
be utilized in subsequent rearrangement reactions.
128
Treatment of oxaziridine 174 with catalytic
copper(I) salts favors formation of a benzylic stabilized radical
that can subsequently cyclize to form products 176–178 (Scheme 24b).
Scheme 24
Transition-Metal-Catalyzed
β-Scission Reactions of Oxaziridines
Other groups have recognized the synthetic potential of
intramolecular
radical cyclizations for generating complex molecules in a stereodefined
manner. Black and co-workers used diastereomerically pure oxaziridines
such as 179 to generate bicyclic amide 180 in high yield (Scheme 25).
129
In this transformation, the initially formed nitrogen-centered
radical cyclizes onto the olefin, followed by attack at the phenyl
ring. Subsequent amide formation gives the product and regenerates
the copper(I) catalyst. This rearrangement was used to generate [5,5]-,
[5,6]-, and [5,7]-bicyclic ring alkaloids by changing the length of
the tethered olefin in the starting material.
Scheme 25
Alkaloid Synthesis
by Transition-Metal-Catalyzed Oxaziridine Rearrangement
3.4
Cycloadditions
The central ring of
an oxaziridine is composed of three different types of bonds; in principle,
formal cycloaddition reactions involving cleavage of the C–O,
C–N, and N–O bonds are all feasible and would lead to
different classes of heterocyclic products. Much of the literature
involving cycloadditions of oxaziridines focuses on cleavage of the
C–O bond, primarily because the propensity of oxaziridines
to rearrange to nitrones under Brønsted and Lewis acidic conditions
has been recognized since Emmons’ original description of these
compounds.
10
Many early reports focus on
cycloaddition reactions with heterocumulenes.
130
Recently, however, methods to promote synthetically useful
cycloadditions involving cleavage of the C–N and N–O
bonds of oxaziridines have also been reported.
3.4.1
Dipolar
Cycloadditions
The thermal
rearrangement of oxaziridines to nitrones has been the subject of
extensive investigation.
117
Given the numerous
synthetic applications of 1,3-dipolar cycloaddition reactions, there
has been considerable interest in the design of tandem rearrangement–dipolar
cycloaddition reactions that begin with oxaziridine substrates. In
1986, Padwa and co-workers described the intramolecular 1,3-dipolar
cycloaddition of a nitrone generated from an oxaziridine bearing a
tethered alkene.
131
In this reaction, oxaziridine 184 was heated to generate the putative nitrone 186,
which was trapped by the pendant alkene to yield isoxazolidine 185 in 86% yield (eq
36). The same product
could also be formed in high yield from the independently prepared
nitrone 186, thus supporting its role as an intermediate.
The authors also established that intermolecular cycloadditions were
possible with electron-deficient alkenes to give 5-substituted isoxazolidines.
36
Davis et al. also postulated that
nitrones might be intermediates in the thermal decomposition of N-sulfonyloxaziridines,
but due to their instability, N-sulfonyl nitrones generated by thermal rearrangements
of oxaziridines have not been trapped via dipolar cycloaddition reactions.
The Yoon laboratory, on the other hand, discovered that N-nosyloxaziridine (nosyl
= 4-nitrobenzenesulfonamide) 187 undergoes efficient rearrangement in the presence
of catalytic TiCl4 (Scheme 26).
40
Under these mild conditions, the highly electrophilic N-nosyl nitrone 188 reacts productively
with electron-rich
dipolarophiles to yield 1,2-isoxazolidine 189 with high
cis selectivity.
The isoelectronic rearrangement of oxaziridines
that involves cleavage
of the C–N bond would result in the formation of an unusual
class of 1,3-dipoles called carbonyl imines, the chemistry of which
has not been extensively explored. Huisgen predicted the existence
of these dipoles in 1963,
132
in analogy
to nitrones and carbonyl oxides. The first experimental validation
of the ability of these compounds to undergo dipolar cycloaddition
reactions was reported by the Yoon laboratory in 2010. N-Nosyloxaziridine 187 rearranges
to carbonyl imine 190 in the presence of the bulky scandium complex [Sc(tmbox)Cl2]SbF6;
cycloaddition with a range of π systems
results in the formation of 1,2-isoxazolines (191) with
high trans selectivity.
133
Together with
the TiCl4-catalyzed nitrone rearrangement, these cycloadditions
provide straightforward access to either cis- or trans-substituted N-nosylisoxazolidines.
Selective cleavage of the N–O
bond or removal of the N-nosyl moiety can be accomplished
under orthogonal conditions (Scheme 27).
Scheme 26
Complementary Dipole Formation from N-Sulfonyloxaziridines
Scheme 27
Orthogonal Isoxazolidine Deprotection
A number of cycloadditions
have also been reported utilizing N-tert-butyl-3-phenyloxaziridine 2 that involve
insertion
of a π-unsaturated system into
the C–O bond of the oxaziridine to yield heterocyclic products.
Troisi and co-workers demonstrated that electron-rich alkenes react
with oxaziridine 2 to give 3,5-diarylisoxazoline 198 with moderate to excellent cis
selectivity (eq 37).
134
Aryl
135
and aliphatic
136
terminal alkynes are also competent reaction partners; however,
product distributions are highly variable, depending on the substrate.
Internal alkynes and benzonitriles
137
have
also been utilized to yield 5-acylisoxazolines and 2,3-dihydro-1,2,4-oxadizole
products, respectively. Kivrak and Larock demonstrated that benzynes
can insert into the C–O bond of a range of N-alkyl-3-aryloxaziridines to yield dihydrobenzisoazoles
(eq 38).
138
37
38
3.4.2
Oxyaminations
Cycloaddition reactions
involving the cleavage of the N–O bond of an oxaziridine have
received increasing attention in the past several years. When the
reaction partner involved in the cycloaddition is an alkene, the product
is a 1,3-oxazolidine that can be considered to be a protected amino
alcohol. However, direct, uncatalyzed oxyamination reactions between
oxaziridines and olefinic substrates are quite rare. Desmarteau reported
that electron-deficient 1,1-difluoroalkenes react with perfluoro oxaziridine 202 to
furnish 1,3-oxazolidine 203 in good yield
(eq 39),
139
but only
electron-deficient alkenes undergo this unusual aminohydroxylation.
Simple olefins react with 202 to give epoxides, which
is an example of the oxygen transfer typically associated with these
oxaziridines. More recently, Dmitrienko observed the unexpected formation
of aminal 205 upon reaction of N-sulfonyloxaziridine 23 and 2,3-dimethylindole during
a model study toward the
total synthesis of the antitumor alkaloid FR900482 (eq 40).
140
The scope of this reaction
is also limited to a very narrow substrate range; only extremely electron-rich
2,3-dialkylindoles were reported to give the aminohydroxylation product.
39
40
In 2007, the Yoon laboratory reported that copper(II) complexes
catalyze the oxyamination of a range of alkenes using N-sulfonyloxaziridines as the
terminal oxidant. A range of olefins,
including styrenes, allylsilanes, enol ethers, and 1,3-dienes, were
found to be excellent substrates, and the aminal products are formed
with complete regioselectivity in each case (eq 41).
141
Reactions involving unsymmetrical
1,3-dienes proceed with good to excellent olefin selectivity, and
only mono-oxyamination is observed. The resulting allylic 1,2-amino
alcohols can be easily elaborated to a variety of synthetically useful
complex amine-containing compounds.
142
41
Yoon proposed the mechanism for this transformation as shown
in
Scheme 28. Upon coordination to a copper catalyst,
oxaziridine 23 becomes activated toward substrate-induced
homolysis of the N–O bond. Thus, attack of the olefin onto
the copper-activated oxaziridine gives intermediate 209 with a benzylic radical and
copper(III)-stabilized sulfonamide.
Cyclization of the Cu(III)–sulfonamide then forms the aminal
product 207 and regenerates the copper catalyst.
143
Scheme 28
Proposed Mechanism of Oxaziridine-Mediated
Oxyamination
An enantioselective
version of this reaction catalyzed by a chiral
bis(oxazoline)copper(II) complex has been reported. Oxyamination of
a variety of styrenes proceeded in good yield and modest to good enantioselectivity
in the presence of commercially available copper(II) hexafluoroacetylacetonate
[Cu(F6acac)2)] and (R,R)-Ph-Box 210 (eq 42).
144
The amino alcohol products that result from
this protocol are highly crystalline, and very highly enantioenriched
amino alcohols can easily be prepared by recrystallization. Thus,
while the stereocontrol available from this method are lower than
those generally observed in the Sharpless aminohydroxylation reaction,
145
the regioselectivity is much higher for styrenes.
42
The addition of exogenous halide salts to the copper(II)–aminooxygenation
reaction greatly enhances reaction rates.
143
Yoon et al. have hypothesized that the addition of chloride anion
results in the formation of an anionic halocuprate(II) complex in
situ, which may be better able to stabilize the copper(III) intermediate
invoked in Scheme 28. The greater reactivity
available using these conditions enables the oxyamination of less
reactive substrates with higher yields and shorter reactions times.
The use of a halocuprate(II) catalyst also allows the use of the less
reactive symmetrical 3,3-dimethyloxaziridine 211 (eq 43), which circumvents some of
the difficulties associated
with purification and analysis of the diastereomeric aminal products
previously reported. These halocuprate conditions have been applied
to the oxyamination of tryptamine derivatives as an efficient route
to enantiomerically enriched 3-aminopyrroloindolines,
146
a common functional motif present in numerous
biologically active indole alkaloids (Scheme 29).
43
Scheme 29
Synthesis of Enantioenriched 3-Aminopyrroloindolines
The Yoon laboratory later discovered
that iron salts are also effective
catalysts for the intermolecular addition of the N–O bond of
the oxaziridine across a range of styrenes, dienes, and aliphatic
olefins.
147
However, the regiochemical
outcome of this reaction is opposite that observed in copper-catalyzed
reactions; oxazolidine 217, which bears the amino functionality
on the less-substituted carbon, is the exclusive regioisomer formed
(eq 44).
44
A highly enantioselective
iron-catalyzed oxyamination using this
strategy was reported in 2012. Utilizing a combination of a highly
electron-deficient iron(II) triflimide salt and bis(oxazoline) ligand 218, the oxazoline
product 217 was produced in
good yield and exceptional enantioselectivity (eq 45).
148
Notably, this allows complementary
access to enantioenriched chiral amino alcohols utilizing copper and
iron bis(oxazoline) catalysts and is also a rare example of a highly
enantioselective oxidative iron-catalyzed reaction.
45
Lewis base catalysts have also been utilized to achieve formal
[3 + 2]-cycloaddition reactions of N-sulfonyloxaziridines to yield oxazolin-4-ones
via N–O bond
cleavage. Lui, Feng, and co-workers demonstrated that chiral N-heterocyclic carbene
222 can be used to generate
reactive zwitterionic enolates from disubstituted ketenes to produce
the oxazolin-4-one 221 in high yield and ee (Scheme 30, eq 46).
149
The oxaziridine
is also resolved over the course of the reaction and can be recovered
in varying levels of enantioselectivity depending on the substrate.
The authors propose a mechanism that involves addition of the zwitterionic
enolate 227 to the electrophilic oxygen of the oxaziridine
to give intermediate 228 and the imine 229, which can subsequently react to form the
cyclic product and regenerate
the catalyst (Scheme 31). More recently, Dong
et al. reported the oxyaminations of azlactones with oxaziridines
utilizing a chiral bis-guanidinium salt.
150
The reaction affords oxazolin-4-ones with exceptional enantioselectivities
and results in the kinetic resolution of a range of oxaziridines with
high S factors (Scheme 30,
eq 47).
Scheme 30
Chiral Lewis Base-Catalyzed Cycloadditions
Scheme 31
Mechanistic Proposal for Lewis Base-Catalyzed
Cycloaddition
4
Concluding Remarks
The chemistry of oxaziridines has developed
in many diverse and
unexpected directions over the past 6 decades. Initial interest in
the unique structural and physical properties of these strained heterocyclic
ring compounds became overshadowed in the 1980s by the recognition
that electron-deficient oxaziridines could be convenient, bench-stable,
neutral sources of electrophilic oxygen. The use of oxaziridines in
oxygen atom transfer reactions continues to be the most broadly appreciated
application of oxaziridine chemistry. However, many of the most recent
new methods involving oxaziridines have shown that their reactivity
can be perturbed in order to achieve reactions involving nitrogen
atom transfer, oxyamination, cycloaddition reactions, and skeletal
rearrangement reactions. The use of exogenous catalysts to control
the stereoselectivity, regiochemistry, and chemoselectivity of these
reactions will inevitably continue to be a focus of innovation in
this area.
One reasonable conclusion that can be drawn from
the fact that
such a broad diversity of new oxaziridine-mediated reactions has been
discovered in the past few decades is that the synthetic potential
of oxaziridine chemistry has yet to be fully revealed. The subtle
sensitivity of oxaziridines toward the steric and electronic properties
of their substituents suggests that structurally modified oxaziridines
with different chemoselectivity profiles or superior rates of reactivity
with organic substrates may yet be discovered. The success that theoretical
computation has enjoyed in rationalizing and predicting the reactions
of oxaziridines will be particularly useful in these efforts. Thus,
a combination of rational mechanistic investigation and empirical
serendipitous discovery will continue to be important as interest
in the chemistry of these intriguing heterocycles continues to grow.