Metal-free, aerobic dioxygenation of alkenes using hydroxamic acids

Article abstract of DOI:10.1002/anie.201000843

(Chemical equation presented) One dioxygenation please, hold the metal: In the presence of either oxygen or air as the sole oxidant and external oxygen atom source, a variety of unsaturated hydroxamic acids afford cyclic hydroxamates that are readily converted into 1,2-diols, with the potential for high levels of reaction stereocontrol.

Full text of DOI:10.1002/anie.201000843

Angewandte
Chemie
DOI: 10.1002/anie.201000843
Synthetic Methods
Metal-Free, Aerobic Dioxygenation of Alkenes Using Hydroxamic
Acids**
Valerie A. Schmidt and Erik J. Alexanian*
Methods for achieving the vicinal difunctionalization of
alkenes greatly facilitate the preparation of functionalized
organic compounds. Examples of useful transformations
include alkene dioxygenations,[1] aminooxidations,[2] and dia-
minations,[3] with many notable recent developments employ-
ing palladium catalysis. A common drawback to these
processes is the use of precious and/or toxic transition-metal
catalysts. We report herein a convenient, general method for
alkene dioxygenation that utilizes oxygen as an environ-
mentally friendly and inexpensive oxidant, while circum-
venting the use of metal catalysts.
As a persistent triplet diradical in its ground state,
molecular oxygen reacts rapidly with carbon-centered radi-
cals.[4] This mode of reactivity was witnessed by Gomberg
during his historic studies on the first organic free radical,
Scheme 1. Spontaneous aerobic radical cyclization of stilbene-substi-
triphenylmethyl,[5] and is an important step in classical radical
tuted tert-butyl hydroxamic acid 1 as reported by Perkins and co-
autoxidation.[6] Radical oxygenation has proven to be of value
in modern organic synthesis, especially in cases where the
generation of carbon-centered radicals proceeds in a regio-
selective manner. For example, radical decarboxylation,[7]
dehalogenation,[8] demercuration,[9] and carbocyclization[10]
processes have all utilized molecular oxygen to selectively
deliver radical oxidation products.
During their pioneering work on the fundamental reac-
tivity of amidoxyl radicals with alkenes, Perkins and co-
workers observed a single remarkable example of an ami-
doxyl radical cyclization followed by oxygenation
(Scheme 1).[11] While attempting to prepare the highly con-
jugated stilbene-substituted tert-butyl amidoxyl radical 2, the
parent hydroxamic acid 1 underwent spontaneous oxidation
and intramolecular cyclization followed by radical oxygen-
ation to deliver hydroperoxide 3 as a mixture of diastereo-
mers.[12] These nitroxyl radicals, which contain electron-
withdrawing acyl groups, are destabilized relative to persis-
tent dialkyl nitroxyl radicals (e.g. TEMPO, 2,2,6,6-tetrame-
thylpiperidine 1-oxyl),[13] and can be generated by oxidation
of N-aryl or alkyl hydroxamic acids under mild conditions.[14]
We envisioned an alkene cyclization with a tethered
amidoxyl radical that is formed in situ from readily obtained
workers.[11]
N-aryl hydroxamic acids, and subsequent reaction with
molecular oxygen, as a potentially general approach to the
dioxygenation of alkenes (Scheme 2). This strategy utilizes
amidoxyl radicals as a substitute for highly reactive alkoxy
radicals,[15] and allows the production of vicinal diols by
À
subsequent facile reductive cleavage of the N O bond.
Furthermore, this method differentiates the oxygen atom
functionality delivered to the alkene, which is difficult using
current dioxygenation methods.
Scheme 2. Proposed alkene dioxygenation using N-aryl hydroxamic
acids and O2.
We began our studies with N-phenyl hydroxamic acid 4.
To facilitate cyclization, initial experiments explored the use
of simple, inexpensive cobalt salts as catalysts, which assist the
formation of amidoxyl radicals under aerobic conditions.[16]
Treatment of 4 with either 2 mol% Co(OAc)2 or 2 mol%
[Co(acac)3] under one atmosphere of O2 in acetic acid
provided the desired dioxygenated [1,2]-oxazinone 5 in 55
and 54% yield, respectively (Table 1, entries 1 and 2). A
control experiment revealed that dioxygenation proceeded
under 1 atmosphere of O2 alone, in the absence of any metal
catalyst, to afford [1,2]-oxazinone 5 in 80% yield following
[*] V. A. Schmidt, Prof. E. J. Alexanian
Department of Chemistry, The University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599 (USA)
Fax: (+1)919-962-2388
E-mail: eja@email.unc.edu
[**] This work was supported by generous start-up funds provided by
UNC Chapel Hill.
Supporting information for this article including experimental
procedures and product characterization is available on the WWW
under http://dx.doi.org/10.1002/anie.201000843.
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Table 1: Initial aerobic dioxygenation studies.
also participate in the dioxygenation process, as styrene-
substituted hydroxamic acid 12 reacts smoothly to deliver
oxazinone 13 in 63% yield (Table 2, entry 4). We also
prepared a-diallyl hydroxamic acid substrate 14 to explore
the potential for selective oxidation of diene substrates. Upon
heating under one atmosphere of O2 in dimethyl sulfoxide, 14
cyclizes to monoallyl [1,2]-oxazinone product 15 in 75% yield
(Table 2, entry 5). This selectivity is dictated by the intra-
molecular amidoxyl radical cyclization. Oxidation of similar
substrates by using intermolecular protocols would likely lead
to a mixture of mono- and bis-difunctionalization products.
The results presented in Table 1 and Table 2 demonstrate
the unique chemoselectivity of the amidoxyl radical in 6-exo
alkene-cyclization reactions. Oxygen-centered radicals are
generally incapable of providing access to six-membered ring
systems through alkene cyclization reactions, owing to the
marked predominance of 1,5-hydrogen abstraction at the
allylic position.[17] However, we observed no by-products
resulting from these allylic oxidation pathways, which we
attribute to the attenuated reactivity profile of the amidoxyl
radical. The amidoxyl radical thus performs admirably well as
an oxygen-centered radical substitute for the promiscuous
alkoxy radical in this important context.
Entry
Metal
2% Co(OAc)2
Solvent Conditions T [8C]/t [h] Yield [%]
1
AcOH
2% [Co(acac)3] AcOH
1 atm O2
1 atm O2
1 atm O2
1 atm Ar
1 atm O2
60/4
60/4
60/4
60/4
90/9
55[a]
54[a]
80[b]
trace
65[c]
2
3
4
5
None
None
None
AcOH
AcOH
DMSO
[a] Yield determined by GC analysis. [b] Yield of isolated product after
PPh3 workup. [c] Yield of isolated product.
mild in situ reductive work up with PPh3 (Table 1, entry 3).
Under these conditions, no reaction took place under one
atmosphere of Ar (Table 1, entry 4). Substituting dimethyl
sulfoxide for acetic acid as solvent and heating at 908C
directly delivered dioxygenation product 2 in 65% yield
(Table 1, entry 5).
Encouraged by these initial findings, we explored the
generality of this metal-free aerobic alkene dioxygenation in a
variety of synthetic contexts (Table 2). The difunctionaliza-
tion of substrate 6 by 5-exo ring closure proceeded well,
delivering isoxazolidinone 7 in 88% yield (Table 2, entry 1).
Further substitution on the alkene moiety is well-tolerated in
the dioxygenation process, as demonstrated by the successful
reactions involving 1,2-disubstituted and trisubstituted sub-
strates 8 and 10 (Table 2, entries 2 and 3). Conjugated alkenes
To assess the potential for diastereocontrol in the
dioxygenation process, we studied a number of different
substrates (Table 3). b-Phenyl-substituted hydroxamic acid 16
underwent a highly stereoselective 6-exo cyclization, provid-
ing product 17 as a single diastereomer in 62% yield (Table 3,
entry 1). b-Silyloxy substrate 18 performed equally well,
Table 3: Studies of alkene dioxygenation stereoselectivity.[a]
Table 2: Aerobic dioxygenations of alkenyl N-aryl hydroxamic acids[a]
Entry
Substrate
Conditions[b]
Product
Yield [%][c,d]
Entry
Substrate
Conditions[b]
Product
Yield [%][c,d]
62
1
A
(>95:5 d.r.)
1
A
88
69[e]
(>95:5 d.r.)
2
3
4
5
C
A
A
A
66
2
3
4
5
B
C
B
B
(55:45 d.r.)
91[e]
(78:22 d.r.
b:a)
79
63
98
(60:40 d.r.)
(66:33 d.r.
b:a)
75
(62:38 d.r.)
64[e]
(84:16 d.r.
b:a)
[a] All reactions run in 0.1m solvent, 1 atm O2, 3–40 h. [b] Conditions
A: AcOH, 608C, PPh3 work up. B: DMSO, 908C. C: DMSO, 608C, PPh3
workup. [c] Yield of isolated product. [d] The diastereomeric ratios were
determined by 1H NMR spectroscopic analysis of the crude reaction
mixtures.
[a]–[d] See Table 2. [e] Reactions initiated with 10 mol% dilauroyl
peroxide.
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delivering the fully differentiated masked triol 19 in 69%
yield and > 95:5 d.r. (Table 3, entry 2). This reaction was
initiated by the addition of dilauroyl peroxide, as the reaction
in the absence of an initiator was slow. Although not
necessary for the majority of substrates, we found this to be
a simple way to increase reaction rates, as required.
production of alkylhydroperoxides by isolating and character-
izing the parent hydroperoxide of dioxygenation product 11
(Table 2, entry 3).[20] Subsequent reduction by Me2S, formed
in situ from the disproportionation of dimethyl sulfoxide[21] or
added PPh3, produces dioxygenation product 31.
Access to 1,2-diols is readily accomplished through
À
We also explored the potential of the dioxygenation
process for reactions involving cyclic alkenes. Cyclopentenyl
substrate 20 underwent 6-exo cyclization to provide [5,6]-cis-
fused product 21 as a 78:22 mixture of b:a hydroxy
diastereomers in high yield (91%; Table 3, entry 3). Difunc-
tionalization of cyclopentenyl substrate 22 gave [5,5]-cis-fused
product 23 in 98% yield, also favoring the b-hydroxy
diastereomer (Table 3, entry 4). Cyclohexenes are also
viable substrates for stereoselective dioxygenation, as
hydroxamic acid 24 delivered [6,6]-cis-fused bicyclic oxazi-
none 25 as an 84:16 mixture of b:a hydroxy diastereomers
(Table 3, entry 5). These results indicate that the aerobic
dioxygenation of cyclic substrates favors trans-alkene difunc-
tionalization, providing a useful alternative to cis-selective
metal-catalyzed alkene dioxygenation processes.[1]
We further hypothesized that the dioxygenation could be
promoted by air alone. Remarkably, dioxygenation of alkenyl
hydroxamic acid 4 at 608C in acetic acid delivered [1,2]-
oxazinone 5 in four hours using one atmosphere of air as the
sole oxidant and external oxygen atom source [Eq. (1)]. To
the best of our knowledge, this represents the first such
example of a metal-free dioxygenation of simple alkenes
using air.
reduction of the N O bond. For example, we have developed
a one-pot alkene dihydroxylation reaction by adding zinc
metal directly into the reaction mixture prior to work-up. As
shown in Equation 2, substrate 6 undergoes aerobic dioxyge-
À
nation and in situ reduction of the N O bond with zinc to
produce diol 32 in 83% yield.
In conclusion, we have developed a metal-free, aerobic
dioxygenation of alkenes using hydroxamic acids. This
reaction avoids the use of precious transition-metal catalysts
that are typically required in related difunctionalization
processes and employs oxygen or air as green oxidants and
external oxygen atom sources. The dioxygenation reaction is
applicable to a wide range of unsaturated substrates and
affords dioxygenation products with differentiated oxygen
atom functionality, which is a unique feature of this process.
This method also exhibits the potential for high reaction
stereoselectivity, and results in trans difunctionalization with
cyclic alkenes, complementing transition-metal-catalyzed cis-
selective dioxygenation reactions. The mild reaction condi-
tions, simple substrate preparation, and generality of this
dioxygenation procedure are attractive aspects for organic
synthesis. Future studies will explore the unique reactivity of
amidoxyl radicals in the development of new reactions and in
complex synthetic applications.
A plausible reaction mechanism is shown in Scheme 3.
Following initiation of the reaction via formation of the
amidoxyl radical, a reversible cyclization produces carbon-
centered radical 28.[18] This intermediate reacts with oxygen to
deliver alkylhydroperoxy radical 29, which subsequently
performs a hydrogen atom abstraction from the substrate
hydroxamic acid,[19] generating amidoxyl radical 27 and
affording alkylhydroperoxide 30. We have verified the
Received: February 10, 2010
Revised: March 8, 2010
Published online: May 10, 2010
Keywords: alkenes · difunctionalization · oxygen ·
radical reactions · sustainable chemistry
.
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