Metal-free oxyaminations of alkenes using hydroxamic acids

Article abstract of DOI:10.1021/ja204255e

A radical-mediated approach to metal-free alkene oxyamination is described. This method capitalizes on the unique reactivity of the amidoxyl radical in alkene additions to furnish a general difunctionalization using simple diisopropyl azodicarboxylate (DIAD) as a radical trap. This protocol capitalizes on the intramolecular nature of the process, providing single regioisomers in all cases. Difunctionalizations of cyclic alkenes provide trans oxyamination products inaccessible using current methods with high levels of stereoselectivity, complementing cis-selective oxyamination processes.

Full text of DOI:10.1021/ja204255e

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Metal-Free Oxyaminations of Alkenes Using Hydroxamic Acids
Valerie A. Schmidt and Erik J. Alexanian*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S Supporting Information
b
Scheme 1. Alkene Difunctionalizations Using
N-Aryl Hydroxamic Acids
ABSTRACT: A radical-mediated approach to metal-free
alkene oxyamination is described. This method capitalizes
on the unique reactivity of the amidoxyl radical in alkene
additions to furnish a general difunctionalization using
simple diisopropyl azodicarboxylate (DIAD) as a radical
trap. This protocol capitalizes on the intramolecular nature
of the process, providing single regioisomers in all cases.
Difunctionalizations of cyclic alkenes provide trans oxyami-
nation products inaccessible using current methods with
high levels of stereoselectivity, complementing cis-selective
oxyamination processes.
icinal amino alcohols are highly valuable compounds in
V
chemical synthesis, comprising a multitude of biologically
active compounds and natural products.1 Alkene oxyamination
enables the direct synthesis of 1,2-aminoalcohols from simple
unsaturated hydrocarbons and is, therefore, a most useful
synthetic transformation for accessing this important motif.2
There are a number of synthetic methods capable of facilitating
alkene oxyamination; however, these processes commonly rely
on the use of precious and/or toxic transition-metal catalysts3 or
hypervalent iodine(III)-based oxidants.4 In addition, the control
of oxyamination regioselectivity is often a major challenge using
metal-catalyzed intermolecular difunctionalization protocols.
Herein, we report a transition-metal-free approach to alkene oxya-
mination employing easily prepared hydroxamic acids and com-
mercially available azodicarboxylates. This approach offers high
levels of reaction regio- and stereoselectivity and constitutes a
general approach to the direct trans oxyamination of cycloalk-
enes, complementing cis-selective metal-catalyzed protocols.
Our radical-based approach to alkene oxyamination is out-
lined in Scheme 1. Readily prepared N-aryl hydroxamic acids are
easily converted to amidoxyl radicals upon exposure to mild
oxidants or radical initiators.5 These reactive species are then capable
of addition to alkenes, producing an intermediate carbon-cen-
tered radical. We have previously shown that interception of this
carbon-centered radical with molecular oxygen provides a radi-
cal-based approach to alkene dioxygenation.6 We hypothesized
that simple substitution of molecular oxygen for an N-atom
radical trap could provide the analogous oxyamination product.
Importantly, the regioselectivity of this process should be easily
controlled by the intramolecular addition step of the tethered
amidoxyl radical.
1 equiv of diisopropyl azodicarboxylate (DIAD) delivered the
isoxazolidinone oxyamination product 2 in 88% isolated yield
(eq 1). While the reaction utilizing 1 equiv of DIAD was succes-
sful, reaction using an excess of DIAD (3 equiv) proceeded in
higher yield (94% vs 88%) and a much shorter reaction time (5 vs
27 h). Reactions of substrate 1 employing other simple azodi-
carboxylates such as diethyl azodicarboxylate (DEAD) and di-
tert-butyl azodicarboxylate (DTAD) were also successful, deli-
vering the corresponding oxyamination products in 92% and
68% yield, respectively.8 Notably, this alkene difunctionalization
proceeded without any additional reagents. We attribute this reac-
tivity to the formation of a small amount of the amidoxyl radical
(autoxidation) prior to the start of the reaction, capable of
initiating the radical chain process.9
We next explored the scope of this metal-free alkene oxyami-
nation utilizing a variety of unsaturated hydroxamic acids as
substrates (Table 1). The difunctionalization of hydroxamic acid
3 involving 6-exo ring closure proceeded efficiently, affording
oxazinone 4 in 83% yield (Table 1, entry 1). This reaction was
initiated by the addition of commercially available, low tempera-
ture radical initiator V-65 (2,20-azobis(2,4-dimethyl valeronitrile)),
as reaction without added initiator was slow. Although not neces-
sary in reactions with most substrates, we found this to be a simple
way to increase reaction rates, as desired. Reactions involving 1,
We commenced our studies utilizing azodicarboxylates as an
N-atom source, as these readily available compounds have
demonstrated ability as carbon-centered radical traps.7 We began
by exploring the oxyamination of unsaturated hydroxamic acid 1.
Heating this substrate in DMSO at 60 °C in the presence of
Received: March 10, 2011
Published: July 06, 2011
r
2011 American Chemical Society
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Table 1. Oxyaminations of Alkenyl N-Aryl Hydroxamic
Scheme 2. Selective Reduction of Difunctionalization
Products
Acidsa
Table 2. Stereoselective Oxyaminations of Cycloalkenesa
a All reactions run 0.5 M in DMSO with 3 equiv of DIAD at 60 °C.
b Yields of isolated product. c The diastereomeric ratios were determined
by 1H NMR spectroscopy of crude reaction mixtures. d 10 mol % V-65
azo initiator added at 40 °C. e Reaction temp 40 °C. f 10 mol % dilauroyl
peroxide (DLP) initiator added.
a All reactions run 0.5 M in DMSO with 3 equiv of DIAD at 60 °C.
b Yields of isolated product. c The diastereomeric ratios were determined
by 1H NMR spectroscopy of crude reaction mixtures.
1- and 1,2-disubstituted alkenes were also successful, as demon-
strated by the reactions of substrates 5 and 7, respectively
(Table 1, entries 2 and 3).10 Conjugated alkenes also participate
in the oxyamination process, as styrenyl substrate 9 afforded
oxazinone 10 (Table 1, entry 4). In order to test the functional
group compatibility of the oxyamination, we prepared substrate
11 containing a free primary hydroxyl group. Reaction of 11
afforded isoxazolidinone 12 in 64% yield, demonstrating the
compatibility of this mild, radical-mediated protocol with func-
tional groups susceptible to oxidation (Table 1, entry 5). The
intramolecular nature of the oxyamination process also permits
chemoselective single difunctionalization of diene substrates, as
demonstrated by the reaction of R-diallyl hydroxamic acid 13
(Table 1, entry 6). The utilization of common intermolecular
oxyaminations would likely lead to mixtures of mono- and bis-
difunctionalized products.
one-pot cleavage of the NꢀO and NꢀN bond of 2, delivering 16
in 63% yield.12
In contrast to the variety of methods available for cis-selective
oxyamination, there are few methods capable of the direct,
stereoselective trans oxyamination of cycloalkenes.13 An intra-
molecular oxyamination process using unsaturated O-alkyl hy-
droxamates by Wardrop is a notable exception, though this
process requires stoichiometric quantities of hypervalent iodine-
(III) reagents.4b In order to assess the stereoselectivity of the
oxyamination process using cycloalkenes, we studied the oxya-
mination of a number of cycloalkenyl hydroxamic acids
(Table 2). Our studies began with the study of cyclopentenyl
substrate 17, which delivered trans oxyamination product 18 as a
single diastereomer in 80% yield (Table 2, entry 1). Both cyclo-
hexenyl hydroxamic acid 19 and cycloheptenyl substrate 21 also
produced trans difunctionalization products in high yield as single
diastereomers (Table 2, entries 2ꢀ3). The difunctionalization of
Following the oxyamination process, direct reductive cleavage
of the NꢀO or NꢀN bond is easily accomplished to provide the
acyclic difunctionalization product (Scheme 2). For example,
selective mild reduction of the isoxazolidinone NꢀO bond of 2
proceeds using Zn in a 1:1 AcOH/H2O solvent mixture. Reduc-
tion using Raney Ni under ultrasonic conditions11 results in
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Scheme 3. Cascade Cyclization of Triene Substrate 25
facile formation of these species from simple hydroxamic acids, as
constituting a promising approach to radical-mediated organic
synthesis harnessing the powerful synthetic potential of oxygen-
centered radicals.
In conclusion, we have developed a metal-free approach to
alkene oxyamination using hydroxamic acids and simple azodi-
carboxylates. These reactions proceed without the use of transi-
tion-metal catalysts and/or hypervalent iodine(III) reagents
common to related alkene difunctionalization processes. This
tethered oxyamination reaction is applicable to a wide range of
unsaturated substrates, delivering single regioisomers in all cases,
which is often a challenge using intermolecular protocols. In
addition, this process exhibits high trans-stereoselectivity using
cycloalkene substrates, complementing transition-metal-catalyzed
cis-selective oxyaminations. Initial extensions of the radical-
mediated difunctionalization to multibond-forming cascade
processes are also described. Future work will continue to harness
the unique reactivity of the amidoxyl radical in new synthetic
reaction development, as well as explore applications in complex
molecule synthesis.
cyclic substrates is also not limited to 5-exo cyclizations, as cyclo-
pentenyl substrate 23 reacted to provide product 24 as a single
diastereomer, albeit in lower yield (52%, Table 2, entry 4).
This highly trans-selective radical-mediated oxyamination of
cycloalkenes therefore complements cis-selective transition-
metal-catalyzed protocols. In addition, the tethered nature of the
difunctionalization processes described in Tables 1 and 2 facil-
itates the production of single regioisomers of the alkene
difunctionalization products, which is an important advantage of
the present method. Control of oxyamination regioselectivity
using sterically or electronically unbiased alkenes is a major
challenge using common transition-metal-catalyzed processes.14
Furthermore, current methods for intramolecular alkene oxya-
mination involve cyclizations of N-atom functionality. This
oxyamination using unsaturated hydroxamic acids involves initial
O-atom alkene addition, providing access to products of opposite
regioselectivity.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and spectral data for all new compounds are provided.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
eja@email.unc.edu
’ ACKNOWLEDGMENT
This work was supported by generous start-up funds provided
by UNC Chapel Hill.
Radical-mediated cascade reactions of polyunsaturated com-
pounds have long served as outstanding synthetic platforms for
the rapid generation of molecular complexity.15 As the oxyami-
nation protocol involves carbon-centered radicals as intermedi-
ates, we hypothesized that it may be possible to perform cascade-
type sequences by inserting a carbonꢀcarbon bond-forming step
prior to final carbon-centered radical trapping by the azodicar-
boxylate. Our studies have initially focused on triene hydroxamic
acid substrate 25 (Scheme 3). Upon heating 25 at 60 °C in
DMSO in the presence of 1.2 equiv of DIAD, we isolated desired
cis-fused bicyclic isoxazolidinone 30 in good yield. A mechanistic
proposal is shown. Following amidoxyl radical formation, rever-
sible alkene cyclization can produce isoxazolidinone 27. Inter-
mediate 27 is well positioned for a subsequent CꢀC bond-
forming addition step, which is followed by azodicarboxylate
addition to deliver 30.
Notably, this cascade process is a rare example of a synthetic
transformation capable of the construction of three distinct bond
types in a single reaction: CꢀO, CꢀC, and CꢀN. The capability
of this radical-based approach to oxyamination to generate
functionalized, complex products via cascade sequences is a
useful feature uncommon to transition-metal-mediated or ionic
oxyamination processes.16 We view the controlled reactivity of
amidoxyl radicals in alkene additions, particularly in light of the
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