Metal-free, aerobic dioxygenation of alkenes using simple hydroxamic acid derivatives

Article abstract of DOI:10.1021/ja206306f

The dioxygenation of alkenes using molecular oxygen and a simple hydroxamic acid derivative has been achieved. The reaction system consists of readily prepared methyl N-hydroxy-N-phenylcarbamate and molecular oxygen with a radical initiator, offering an alternative to common dioxygenation processes catalyzed by precious transition metals. This transformation capitalizes on the unique reactivity profile of hydroxamic acid derivatives in radical-mediated alkene addition processes.

Full text of DOI:10.1021/ja206306f

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pubs.acs.org/JACS
Metal-Free, Aerobic Dioxygenation of Alkenes Using Simple
Hydroxamic Acid Derivatives
Benjamin C. Giglio, 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 Dioxygenation Using N-Aryl Hydroxamic
Acids
ABSTRACT: The dioxygenation of alkenes using molecu-
lar oxygen and a simple hydroxamic acid derivative has been
achieved. The reaction system consists of readily pre-
pared methyl N-hydroxy-N-phenylcarbamate and molecular
oxygen with a radical initiator, offering an alternative to
common dioxygenation processes catalyzed by precious
transition metals. This transformation capitalizes on the
unique reactivity profile of hydroxamic acid derivatives in
radical-mediated alkene addition processes.
irect dioxygenation of alkenes is a valuable synthetic tool for
D
the preparation of 1,2-diol derivatives, which have high
utility in organic synthesis. There are a number of transition-
metal-catalyzed processes capable of achieving this goal.1 A
common drawback to these methods is the requirement of toxic
and/or expensive transition metals. In an effort to develop a
metal-free direct dioxygenation of alkenes using molecular oxy-
gen or air as the sole oxidant, we recently developed an aerobic
intramolecular dioxygenation of alkenes using unsaturated hy-
droxamic acids.2 This reaction utilizes the amidoxyl radical as a
synthetic substitute for the typically highly reactive oxygen-
centered radical3 and provides differentiated diols as cyclization
products from a variety of tethered alkenes.
Table 1. Initial Aerobic Dioxygenation Studiesa
In an effort to expand the capabilities of this dioxygenation
process, we targeted the development of a variant proceeding via
an intermolecular addition, as depicted in Scheme 1. This variant
would not require tethering of the hydroxamic acid to the alkene
functionality, facilitating the direct dioxygenation of unsatu-
rated hydrocarbons using molecular oxygen as the sole oxidant.
A number of challenges had to be addressed in developing such a
transformation. For instance, there are no examples of general
synthetic methods proceeding by way of intermolecular addi-
tions of oxygen-centered radicals to alkenes.4,5 Furthermore,
such a process would have a greater activation entropy than the
previously disclosed intramolecular dioxygenation. We report
herein the successful development of an intermolecular direct
aerobic dioxygenation of alkenes employing a simple hydroxamic
acid derivative that overcomes these significant challenges.
We initially explored the intermolecular aerobic dioxygenation
of styrene utilizing simple acylated N-phenylhydroxylamine
derivatives such as N-hydroxy-N-phenylacetamide (1, R = Me)
under conditions similar to those in our previous intramolecular
studies. However, reaction of N-hydroxy-N-phenylacetamide
(1.0 equiv) and styrene (1.2 equiv) under 1 atm O2 at 60 °C
in AcOH with 2.5 mol % dilauroyl peroxide (DLP) as an initiator
led to no observed dioxygenation product. Substituting DMSO
for AcOH did provide the desired dioxygenation product after an
a All of the reactions were run using 1.0 equiv of 2 and 1.2 equiv of
styrene. b Yields of isolated products.
extended reaction time (3 d), albeit in low yield. We next
attempted the dioxygenation using methyl N-hydroxy-N-phe-
nylcarbamate (2), a related simple hydroxamic acid derivative
that is easily obtained by the reaction of N-phenylhydroxylamine
and methyl chloroformate. Under our optimized reaction condi-
tions employing nBuOAc as the solvent,6 the aerobic dioxygenation
of styrene utilizing 2 delivered a single product regioisomer in high
yield following mild in situ workup with Me2S (Table 1, entry 1).7
Our optimization studies revealed that the addition of DLP as an
initiator was not required for the reaction to proceed (entry 2) but
Received: July 7, 2011
Published: August 02, 2011
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2011 American Chemical Society
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did increase the reaction rate. We attribute the reaction in the
absence of the initiator to formation of the amidoxyl radical from 2
via autoxidation processes. The use of solvents employed in our
previously reported intramolecular cyclizations, such as DMSO or
AcOH, decreased the reaction efficiency (entries 3 and 4). The use
of exactly 1.0 equiv of alkene with either 1.0 or 1.2 equiv of 2 led to
reduced yields (entries 5 and 6), which we attribute to side reactions
of styrene. Notably, the aerobic dioxygenation could be run on a
gram scale with no loss in reaction efficiency (92% isolated yield).
We next explored the reaction scope using our optimized
dioxygenation protocol. Styrenes proved to be excellent sub-
strates for the aerobic dioxygenation (Table 2). Both electron-
rich and electron-poor styrenes were dioxygenated in high yield
(entries 1À4). Notably, these reactions all produced a single
differentiated diol regioisomer as the product, as did all of the
other substrates shown in Table 2. Styrenes containing R- or
β-alkyl substitution were also viable substrates (entries 5À7),
with β-methylstyrene favoring the anti dioxygenation product
with a moderate level of stereoselection (78:22 dr). This aerobic,
radical-mediated dioxygenation is also compatible with common
functional groups that are susceptible to oxidation (entry 8). The
bicyclic substrates 2-vinylnapthalene (entry 9) and 1-methylene-
1,2,3,4-tetrahydronapthalene (entry 10) also reacted efficiently
under our dioxygenation protocol. Trisubstituted styrenes were
also excellent substrates under these conditions (entry 11).
We also explored the dioxygenation of a variety of other unsatu-
rated hydrocarbons to define the scope of our current reaction
system (Table 3).8 The heterocyclic substrates 2-vinylthiophene
(entry 1) and 2-(prop-1-en-2-yl)furan (entry 2) yielded dioxy-
genation products in 84 and 48% yield, respectively. A number of
reactions employing dienes were successful (entries 3À5), with
the potential for both 1,2- and 1,4-dioxygenation. Enynes were
viable substrates as well, displaying high chemoselectivity for
difunctionalization of the alkene. The dioxygenation of norbor-
nene proceeded efficiently, delivering a 1.2:1 mixture of product
diastereomers (entry 7). Reactions involving methacrylic acid
(entry 8) and methyl methacrylate (entry 9) additionally demon-
strated the ability of this system to dioxygenate electron-poor
conjugated alkenes.
Table 2. Aerobic Dioxygenation of Styrenic Alkenesa
a All of the reactions were run using 1.0 equiv of 2 and 1.2 equiv of
substrate with [2]0 = 1.0 M in nBuOAc at 60 °C under 1 atm O2 with 2.5
mol % DLP. b Yields of isolated products after Me2S workup. c The
diastereomeric ratio in entry 6 was determined by 1H NMR analysis of
the crude reaction mixture.
Heteroatom-centered radicals are generally considered to be
electron-poor species, favoring additions to more electron-rich
alkenes. In order to study the electronic nature of the putative
amidoxyl radical, we performed a competition experiment involv-
ing the dioxygenation of a 1:1 mixture of p-methoxy- and
p-trifluoromethylstyrene (eq 1). A 2.6:1 ratio of initially formed
hydroperoxides favoring the reaction of the more electron-rich
p-methoxystyrene was observed. This result is consistent with the
amidoxyl radical functioning similarly to other oxygen-centered
radicals as electron-poor species. Thus, the amidoxyl radical can
function as a general synthetic substitute for the promiscuous
alkoxy radical for applications in chemical synthesis.
direct reduction of the NÀO bond and the hydroperoxide
moiety is easily accomplished using Zn metal as the reductant.
For instance, the one-pot dihydroxylation of R-methylstyrene
yielded 2-phenylpropane-1,2-diol in 82% yield (eq 2). Thus,
while a synthetic advantage of this dioxygenation system is the
highly regioselective production of a differentiated diol as demon-
strated in Tables 1À3, aerobic alkene dihydroxylation can also be
readily achieved if desired.
In conclusion, we have developed an aerobic alkene dioxy-
genation method that uses a simple hydroxamic acid derivative
and is applicable to a variety of alkenes. The reaction proceeds
We also developed a simple one-pot protocol for direct
aerobic dihydroxylation of alkenes. Following initial dioxygenation,
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Table 3. Aerobic Dioxygenation of a Variety of Unsaturated
Hydrocarbonsa
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and spectral data for all new compounds. 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.
’ REFERENCES
(1) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
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2010, 132, 13229–13239. For a recent metal-free process using
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(2) (a) Schmidt, V. A.; Alexanian, E. J. Angew. Chem., Int. Ed. 2010,
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(3) (a) Hartung, J. Eur. J. Org. Chem. 2001, 619–632. (b) Zlotorzynska,
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(4) Reactions of isolated amidoxyl radicals with alkenes (anaerobic
conditions) have been shown to provide 1,2-diaddition products in
limited cases. See: Hussain, S. A.; Jenkins, T. C.; Perkins, M. J.; Siew,
N. P. Y. J. Chem. Soc., Perkin Trans. 1 1979, 2803–2808.
(5) Addition of the highly reactive imidoxyl radical derived from
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(6) Other alkyl acetates (e.g., EtOAc) could be employed as the
solvent, but nBuOAc proved to be the most convenient because of its
lower volatility.
(7) The reported yields are relative to the 1.0 equiv of hydroxamic
acid 2 utilized in all of the reactions, as the alkene was employed in slight
excess.
(8) The increased amounts of substrate in the reactions of Table 3
were utilized to ensure adequate concentrations because of the volatility
of several of these compounds.
a All of the reactions were run using 1 equiv of 2 and 5.0 equiv of
substrate with [2]0 = 1.0 M in nBuOAc at 60 °C under 1 atm O2 with 2.5
mol % DLP. b Yields of isolated products after Me2S workup. c The ratios
1
of product regioisomers were determined by H NMR analysis of the
crude reaction mixtures. d 2.0 equiv of substrate was used.
without the use of precious and/or toxic transition-metal cata-
lysts common to related alkene difunctionalization processes and
uses molecular oxygen as the sole oxidant. This process capitalizes
on the synthetic versatility of the amidoxyl radical, which is formed
under mild conditions from simple hydroxamic acid derivatives and
can serve as a useful source of oxygen-centered radicals for chemical
synthesis. Harnessing this unique reactivity has led to the first
example of a general synthetic transformation involving the inter-
molecular addition of an oxygen-centered radical to alkenes. Future
work will continue to explore the use of the amidoxyl radical in the
development of new synthetic reactions, including asymmetric
variants of these difunctionalization processes.
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