Alkene hydrofunctionalization using hydroxamic acids: A radical-mediated approach to alkene hydration

Article abstract of DOI:10.1021/ol5020202

A radical-mediated approach to alkene hydration is described. The present strategy capitalizes on the unique radical reactivity of hydroxamic acids, which are capable of functioning as both synthetically useful oxygen-centered radical species and suitable hydrogen atom-based donors. This reaction manifold has been applied to both alkene hydrations and tandem alkene-alkene carbocyclization processes.

Full text of DOI:10.1021/ol5020202

Letter
pubs.acs.org/OrgLett
Alkene Hydrofunctionalization Using Hydroxamic Acids: A Radical-
Mediated Approach to Alkene Hydration
Benjamin C. Giglio and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: A radical-mediated approach to alkene hydra-
tion is described. The present strategy capitalizes on the
unique radical reactivity of hydroxamic acids, which are
capable of functioning as both synthetically useful oxygen-
centered radical species and suitable hydrogen atom-based
donors. This reaction manifold has been applied to both
alkene hydrations and tandem alkene−alkene carbocyclization
processes.
he hydration of alkenes is a fundamental synthetic
transformation, commonly performed using water and
Scheme 2. An Approach to Alkene Hydration Using
Hydroxamic Acids
T
an acid catalyst.1 Recent efforts have demonstrated the
impressive potential of transition metal or photoredox catalysts
in facilitating catalytic hydrations (or hydroalkoxylations).2
Alternatively, despite the success of heteroatom-centered
radical additions in hydrofunctionalizations, including hydro-
thiolations3 and hydroaminations,4 radical-mediated approaches
to hydration remain undeveloped (Scheme 1).5 It is not
Scheme 1. Alkene Hydrofunctionalization Using
Heteroatom-Centered Radicals
such an H atom transfer would be possible based on the
relatively low O−H bond strength of N-phenyl hydroxamic
acids (∼80 kcal/mol).9 Furthermore, appending additional
unsaturation to the hydroxamic acid substrate could enable
cascade-type radical cyclizations, producing complex polycycles.
Such C−O/C−C/C−H bond-forming cascades would con-
stitute rare examples of synthetic transformations forming three
distinct bond types in a single step.
Our studies commenced with the cyclization of tiglic acid
derived N-phenyl hydroxamic acid 6 (Table 1). Simply heating
the substrate to 60 °C in the presence of 5 mol % of the radical
initiator dilauroyl peroxide (DLP) provided a moderate yield
(65%) of isoxazolidinone product 8. We discovered that the
addition of a substoichiometric amount of methyl N-hydroxy-
N-phenyl carbamate (7), a reagent previously developed in our
laboratory for intermolecular alkene dioxygenations,8c increased
both reaction conversion and yield (entries 1−2). A diverse set
of alternative hydrogen atom donors were studied, including
silanes,10 catechols,7a and thiols;11 however these reactions
provided lower conversions and yields (entries 3−5). The
addition of both DLP and reagent 7 were crucial to the reaction
difficult to understand why this is the case; such a trans-
formation requires two steps with limited precedent: oxygen-
centered radical addition to an alkene6 and hydrogen-atom
transfer from a hydroxyl group to a carbon-centered radical.7
The successful development of a radical-mediated approach to
hydration would require solutions to both of these challenges.
We postulated that hydroxamic acids could enable such a
transformation. We have developed a platform for alkene
functionalization capitalizing on the addition of amidoxyl
radicals to alkenes in intra- and intermolecular processes.8
We sought to develop an approach to alkene hydration by
combining this addition process with H atom transfer from the
hydroxamic acid substrate (Scheme 2). We anticipated that
Received: July 10, 2014
Published: July 28, 2014
© 2014 American Chemical Society
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Letter
(entries 2 and 6). Substrate 11 containing a terminal alkene
reacted sluggishly via a 6-exo cyclization (43% conversion after
42 h) and delivered a low yield of [1,2]-oxazinone product 12
even in the presence of an excess of 7 (1.6 equiv, entry 3). We
hypothesize that the decreased efficiency of this reaction versus
previously reported alkene difunctionalizations using 118d,e is a
consequence of the relatively slow rate of radical hydrogen
atom transfer involved. In contrast, the 6-exo cyclization of
methallyl substrate 13 proceeded to complete conversion and
produced product 14 in 71% yield (entry 4). Cyclopentenyl
substrate 15 afforded 16 in good yield and high diaster-
eoselectivity favoring cis ring fusion (entry 5). The reaction of
methylene cyclohexenyl substrate 17 also proceeded in good
yield and high stereoselectivity (entry 6).
Cascade-type radical cyclizations are among the premier
methods for the rapid construction of complex carbocycles and
heterocycles from unsaturated substrates.12 We postulated that
introducing additional unsaturation to the simple alkenyl
hydroxamic acids of Table 2 would enable the construction
of a variety of complex polycyclic products via cascade-type
cyclizations. As shown in Table 3, we have successfully applied
Table 1. Radical Cyclization of Unsaturated Hydroxamic
Acid 6
a
b
entry
variation from conditions above
none
% conversion
% yield
1
2
3
4
5
6
7
100
80
69
77
73
78
48
90
65
69
55
47
67
38
no 7 added
(Me3Si)3SiH instead of 7
4-tert-butylcatechol instead of 7
tert-dodecylmercaptan instead of 7
no DLP added
no DLP and no 7 added
a
Calculated by 1H NMR spectroscopy of crude reaction mixtures
b
using 1,3,5-trimethoxybenzene as an internal standard. Yield of
isolated product.
(entries 6−7). Reaction conversion in the absence of DLP is
attributed to trace aerobic oxidation of the hydroxamic acid
prior to reaction.
With a viable system for the radical cyclization in hand, we
next surveyed the reaction scope using a diverse set of acyclic
and cyclic alkenyl hydroxamic acids (Table 2). Cyclizations
proceeding via both 5-exo and 6-exo reaction pathways were
possible (entries 1−4). Interestingly, substrates 9 and 17
possessing 1,1-disubstituted alkenes delivered good yields of
isoxazolidinone products even in the absence of reagent 7
Table 3. Cascade-Type Polycyclizations of Unsaturated
Hydroxamic Acids
Table 2. Cyclizations of Alkenyl N-Aryl Hydroxamic Acids
a
Standard reaction conditions: 0.1 mmol of substrate, 5 mol % DLP,
b
c
benzene, 60 °C, 16−72 h. Yield of isolated product. Entries 2 and 3
were performed on a 0.5 mmol scale.
this approach to the synthesis of a number of [5,5]- and [5,6]-
fused and bridged polycyclic compounds. Minor changes in the
standard reaction conditions were required to prevent
decomposition and premature reduction of the intermediate
carbon-centered radical prior to the C−C bond-forming step:
reagent 7 was excluded from these reactions, the reaction
solvent was switched from ClCH2CH2Cl to benzene, and the
cascade reactions were performed at a higher dilution (0.1 M
instead of 0.5 M). The cascade cyclizations of substrates 19 and
21 containing either a terminal or 1,1-disubstituted alkene and
a pendant allyl group delivered [5,5]-cis-fused isoxazolidinone
products 20 and 22, respectively (entries 1 and 2). Cyclo-
hexenyl hydroxamic acid 23 provided an efficient approach to
complex propellane-type bridged isoxazolidinone 24 (entry 3).
The modest diastereoselectivity observed in the cascade
reactions of entries 1−3 is a consequence of the carbon−
carbon bond-forming step. The cascade cyclization of alkynyl
a
Standard reaction conditions: 0.1 mmol of substrate, 5 mol % DLP,
b
0.80 equiv of 7, ClCH2CH2Cl, 60 °C, 16−72 h. Yield of isolated
product. Reaction performed on 0.5 mmol scale with 2.5 mol % DLP
(no 7 required). 1.6 equiv of 7 added.
c
d
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hydroxamic acid 25 provides cis-fused bicyclic isoxazolidinone
26 as a single diastereomer, consistent with this hypothesis
(entry 4).
Indeed, all products in Table 3 exclusively contain cis ring
fusion. The basis for stereoselectivity is easily understood by
considering the likely mechanism for these cascade processes
(Scheme 3). Following an initial, reversible amidoxyl radical
Scheme 3. Reversible Amidoxyl Radical Cyclizations Lead to
cis Ring Fusion in Cascade-Type Processes
Reduction of propellane-type isoxazolidinone 24 provides
substituted hydrindane 35 in high yield.
While our radical-mediated approach to alkene hydration was
successful in a variety of intramolecular contexts, the develop-
ment of intermolecular transformations proved challenging.
This is likely a consequence of the reversibility of the amidoxyl
radical alkene addition, combined with a relatively slow rate of
H atom transfer (see Scheme 2). Nevertheless, we have
obtained a proof-of-principle result for an intermolecular
amidoxyl radical addition by using norbornene as a substrate
under modified reaction conditions (eq 3). This reaction
required extended reaction times (96 h) and did not proceed to
completion. At this stage, our efforts to engage other alkenes
have been unsuccessful.
cyclization, the intermediate carbon-centered radical may be
formed on either the opposite (28) or same (29) face of the
isoxazolidinone ring as the pendant alkene. Intermediate 29
undergoes a fast 5-exo cyclization, whereas isomer 28 is
incapable of alkene addition and reverts to the amidoxyl species
27. This equilibration ultimately leads to exclusive formation of
the cis-fused product.
We hypothesize that the amidoxyl radical cyclizations
involved in the reactions presented herein, and in related
alkene difunctionalizations, are reversible.8 We therefore sought
to provide experimental evidence for this reversibility by
independently demonstrating the viability of a radical
elimination of an amidoxyl species in a ring-opening process
(Scheme 4). Standard radical deiodination of iodide 31 using
In conclusion, we have developed a free-radical-mediated
approach to the formal hydration of alkenes using hydroxamic
acids. This method capitalizes on the unique ability of
hydroxamic acids to participate in both alkene additions and
hydrogen atom transfers. These modes of reactivity have
enabled both simple and cascade-type cyclization processes,
although extensions to intermolecular contexts are currently
limited. The isoxazolidinones produced are easily elaborated to
a variety of mono- and bicyclic products.
Scheme 4. Hydroxamic Acid Formation via a Radical Ring
Opening Process
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures 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
■
(Bu3Sn)2 in toluene at 110 °C delivered ring-opened alkenyl
hydroxamic acid 11 in 29% yield (69% recovered 31). This
result demonstrates the potential for carbon-centered radical 32
to undergo radical ring opening to deliver amidoxyl species 33,
and provides evidence for the reversibility of amidoxyl radical
cyclizations.
The isoxazolidinone products of these cyclization reactions
may be easily elaborated by cleavage of the weak N−O bond.
This reduction can be conveniently performed using palladium-
catalyzed hydrogenation (eqs 1 and 2). For example,
hydrogenation of bicyclic isoxazolidinone 18 (formed from
substrate 17) delivered the formal hydration product 34.
*E-mail: eja@email.unc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by UNC Chapel Hill. We thank Ryan
Quinn (UNC) for experimental assistance.
■
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