Photocatalytic Oxyamination of Alkenes: Copper(II) Salts as Terminal Oxidants in Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b03345

A photocatalytic method for the oxyamination of alkenes using simple nucleophilic nitrogen atom sources in place of prefunctionalized electrophilic nitrogen atom donors is reported. Copper(II) is an inexpensive, practical, and uniquely effective terminal oxidant for this process. In contrast to oxygen, peroxides, and similar oxidants commonly utilized in non-photochemical oxidative methods, the use of copper(II) as a terminal oxidant in photoredox reactions avoids the formation of reactive heteroatom-centered radical intermediates that can be incompatible with electron-rich functional groups. As a demonstration of the generality of this concept, it has been shown that diamination and deoxygenation reactions can also be accomplished using similar photooxidative conditions.

Full text of DOI:10.1021/acs.orglett.8b03345

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photocatalytic Oxyamination of Alkenes: Copper(II) Salts as
Terminal Oxidants in Photoredox Catalysis
Nicholas L. Reed, Madeline I. Herman, Vladimir P. Miltchev, and Tehshik P. Yoon*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: A photocatalytic method for the oxyamination of
alkenes using simple nucleophilic nitrogen atom sources in place
of prefunctionalized electrophilic nitrogen atom donors is reported.
Copper(II) is an inexpensive, practical, and uniquely effective termi-
nal oxidant for this process. In contrast to oxygen, peroxides, and
similar oxidants commonly utilized in non-photochemical oxida-
tive methods, the use of copper(II) as a terminal oxidant in photo-
redox reactions avoids the formation of reactive heteroatom-
centered radical intermediates that can be incompatible with
electron-rich functional groups. As a demonstration of the gener-
ality of this concept, it has been shown that diamination and deoxygenation reactions can also be accomplished using similar
photooxidative conditions.
xyamination of alkenes remains an important problem in
Osynthetic chemistry due to the prominence of amino
alcohol derived subunits in many important classes of bioactive
natural products, pharmaceutical compounds, and chiral
reagents for stereoselective synthesis.1 However, the most exten-
sively developed oxyamination methods, including the Sharpless
aminohydroxylation and its derivatives, require preoxidized,
electrophilic nitrogen donors such as chloramines, iminoiodi-
nanes, or hydroxylamines that can be difficult to synthesize, are
often explosive, and can be challenging to handle because of
their chemical instability. One important objective in oxidative
functionalization methodology has therefore been the develop-
ment of new oxyamination protocols that can be conducted
directly with simple nucleophilic nitrogen and oxygen atom
donors (Figure 1).2
challenge for photoredox chemistry.3 Although many powerful
oxidative photoredox processes have been reported, the
majority have exploited the reactivity of preoxidized electro-
philic group-transfer reagents where some portion of the termi-
nal oxidant is structurally incorporated into the product (e.g.,
halogenation,4 amination,5 or perfluoroalkylation6). In contrast,
an oxyamination protocol using simple heteroatom nucleophiles
requires an “oxidase” strategy7 in which the terminal oxidant
serves as an electron acceptor and not a functional group
donor.8 Unfortunately, terminal oxidants that are suitable for
nonphotochemical reactions can be problematic in photoredox
applications. For instance, molecular oxygen,9 often identified
as an ideal oxidant for organometallic catalysis,10 is an efficient
quencher of the excited states of many photocatalysts11 and
reacts rapidly with the organoradical intermediates that are
ubiquitous in photoredox chemistry.12 Similarly, photoredox
activation of peroxides affords promiscuously reactive oxygen-
centered radicals that can be incompatible with common
electron-rich functional groups.13 Organic oxidants (e.g.,
perhaloalkanes, nitroarenes, amine N-oxides, or arene diazo-
nium salts)14 can avoid these problems but are relatively expen-
sive and produce unattractive stoichiometric byproducts. The
identification of a general terminal oxidant that is free from
these drawbacks would thus represent a significant advance in
photochemical synthesis.
The design of effective net-oxidative transformations is a
fundamental problem in catalysis, but it poses a particular
We began by examining Nicewicz’s pioneering examples of
photocatalytic alkene hydrofunctionalization reactions15
(Scheme 1). In these studies, photooxidation of an alkene
affords an electrophilic radical cation intermediate (1•+).
Subsequent trapping of a heteroatomic nucleophile such as an
Figure 1. Oxyamination reactions with and without preoxidized
nitrogen atom donors.
Received: October 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03345
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
required for conversion to oxazolidone (entry 4), and impor-
tantly, the identity of the oxidant is critical. Other Cu(II) salts
provide diminished yields of the oxyamination product (entries
5 and 6), but an extensive screen of alternate oxidants spanning
several different classes revealed that only Cu(II) oxidants are
effective. For example, PhI(OAc)2, TEMPO, MnO2, and FeCl3
provide no conversion to 6, while air, DDQ, and t-BuOOH
result in extensive decomposition, which is consistent with the
formation of reactive oxygen-centered radical intermediates
(entries 7 and 8). Finally, control experiments validated the
photocatalytic nature of this reaction; no product is observed
in the absence of light or photocatalyst (entries 9 and 10).
The unique suitability of Cu(II) salts in this reaction is
consistent with seminal investigations by Kochi, demonstrating
that Cu(II) salts are exceptionally rapid and efficient oxidants
of carbon-centered radicals.16 Moreover, copper compounds
do not interfere with the photochemistry of common photo-
redox catalysts and have been utilized as co-catalysts in several
recently reported photocatalytic methods.17 Additionally,
Cu(II) salts are attractive, practical stoichiometric oxidants
that are readily handled on the benchtop and removed from a
reaction mixture by simple extraction or filtration through
silica.18 Copper(II) salts are generally less toxic19 and less
expensive than many common organic terminal oxidants.
Although the cost of Cu(TFA)2 itself is unusually high, on par
with common organic oxidants, it can be synthesized from
inexpensive CuCO3 and trifluoroacetic acid, and reactions
using either commercial or freshly prepared Cu(TFA)2 give
identical results.
These optimized conditions proved to be effective on a
gram-scale batch, affording the oxyamination product in 84%
yield (Scheme 2a). A variety of styrenic alkenes undergo facile
oxyamination. The arene could be substituted at all positions
with common functional groups, including halides, ketones,
and aldehydes (Scheme 2b, 8−18). Heteroaryl styrenes can
also undergo oxyamination; while pyridines provide dimin-
ished rates, less basic O and S heterocycles were readily
tolerated (Scheme 2c, 19−21). The diastereoselectivity was
excellent, except in the cases of very electron-rich styrenes (11
and 19).20 Increasing the length of the tether, incorporating
heteroatoms, or substituting the carbon chain had little effect
on the rate of the cyclization (Scheme 2d, 22−24). The
styrene could be substituted on the alkene moiety as well, both
at the α and β positions (Scheme 2e, 25 and 26). Trisub-
stituted aliphatic alkenes, however, instead afforded an allylic
carbamate (27), suggesting that although the excited-state
photocatalyst could oxidize the substrate, the resulting cationic
intermediate undergoes elimination faster than trapping by the
carbamoyl oxygen. Finally, we examined intermolecular oxy-
aminations using simple Boc carbamate as the amine source
(Scheme 2f). Both cis and trans 1,2-disubstituted styrenes
(28 and 29) react with good yields. Interestingly, methyl
cinnamate also underwent oxyamination, despite the presence of
the highly electron-withdrawing ester moiety, affording direct
access to a highly functionalized oxazolidone scaffold (31).
Scheme 3 summarizes several experiments supporting the
mechanism proposed in Scheme 4a. First, subjecting hydro-
amination product 32 to the optimized reaction conditions
resulted in the formation of oxazolidone product 11 in 14%
yield (Scheme 3, eq 1). Thus, the benzylic radical produced by
photooxidation of the arene21 can re-enter the catalytic cycle,
supporting its role as an intermediate in this process. Second,
irradiation of 5a in the presence of 2 equiv of TPPT, but in the
Scheme 1. Diverting Photogenerated Radical Intermediates
toward Net Oxidative Functionalization Reactions
alkyl carbamate results in the generation of a carbon-centered
radical intermediate (2). Interception by a hydrogen atom
donor, often a malononitrile or thiophenol, affords the product
of a redox-neutral hydrofunctionalization reaction (3). A recent
report has also described interception of 2 by catalytic CuCl3 as
an atom-transfer reagent to effect an oxidative aminochlori-
nation.4c We speculated that an appropriate alternative oxidant
could react with this radical to produce a formally cationic inter-
mediate; cyclization with facile loss of tert-butyl cation would
afford oxazolidone products (4), effecting a net-oxidative
oxyamination reaction.
We began by examining the effect of several photocatalysts
and potential terminal oxidants on the oxidative cyclization of
carbamate 5a. Irradiation with a 15 W blue LED for 15 h in the
presence of a commercially available pyrylium photocatalyst
(TPPT, 7) and Cu(TFA)2 as an oxidant affords oxazolidone 6
in 82% yield as a single diastereomer (Table 1, entry 1).
a
Table 1. Effect of Reaction Variables on Oxyamination
yield
(%)
entry
variation from standard conditions
1
2
3
4
5
6
7
none
82
72
5
0
24
7
MesAcrMe+BF4 instead of TPPT
Ir[dF(CF3)ppy]2(dtbbpy)PF6 instead of TPPT
no Cu(TFA)2
−
b
Cu(OTf)2 instead of Cu(TFA)2
Cu(OAc)2 instead of Cu(TFA)2
PhI(OAc)2, TEMPO, MnO2, or FeCl3 instead of
Cu(TFA)2
b
0
c
8
Air, DDQ, or t-BuOOH instead of Cu(TFA)2
0
9
10
no TPPT
no light
1
0
b
a
Unless otherwise noted, all reactions were conducted in degassed
CH2Cl2 and irradiated with a 15 W blue LED flood lamp for 15 h.
1
Yields determined by H NMR analysis of the unpurified reaction
b
mixtures using phenanthrene as an internal standard. No conversion.
c
Substrate decomposition.
Although other strongly oxidizing organic photocatalysts afford
similar results, transition-metal photoredox catalysts with less
positive excited-state reduction potentials are ineffective
(entries 2 and 3). The addition of a terminal oxidant is
B
DOI: 10.1021/acs.orglett.8b03345
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 2. Scope Studies for Photocatalytic Oxyamination Reactions
a
Unless otherwise noted, all reactions were conducted using 2.5 mol % of 7, 1.2 equiv of Cu(TFA)2 in degassed CH2Cl2 and irradiated with a 15 W
b
c
d
blue LED flood lamp for 15−48 h. Isolated yields are reported. Reaction time 48 h. Reaction time 72 h. Reaction time 7 days.
absence of Cu(TFA)2, resulted in complete decomposition of
the substrate without formation of the oxyamination product
(Scheme 3, eq 2). This result is consistent with the hypothesis
that Cu(II) is not merely a terminal oxidant but is intimately
involved in oxidation of the organoradical intermediate, as
expected from Kochi’s studies. Third, the formation of the final
product by loss of tert-butyl cation is consistent with the
observation that while Cbz carbamates cyclize effectively, Moc
carbamates provide no product (Scheme 3, eq 3), in line with
the poor stability of the methyl cation. Finally, because the
reaction requires only 1.2 equiv of Cu(TFA)2, Cu(II) must be
acting as a net two-electron oxidant. It is unclear whether the
Cu(I) intermediate directly turns over the photocatalyst by
oxidation of 7• or disproportionates to Cu(II) and Cu(0). Both
mechanisms would be consistent with the observed precipitation
of copper metal from solution during the course of the reaction.
Oxyamination reactions are representative of a broader class
of synthetically important oxidative alkene difunctionalizations.22
Scheme 3. Experiments Supporting the Proposed
Mechanism
Scheme 4. Working Mechanistic Hypothesis and Extension to Alkene Difunctionalization
a
b
Reactions conducted using MesAcrMe+BF4− as the photocatalyst and Cu(OAc)2 as the terminal oxidant. Reactions conducted using 4 equiv of
alcohol, TPPT as photocatalyst, and Cu(TFA)2 as terminal oxidant.
C
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Sorensen, E. J. Palladium-Catalyzed Ring-Forming Aminoacetoxyla-
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If this Cu(II)-mediated photocatalytic strategy could be
generalized to the use of alternate nucleophilic reaction
partners, it would provide a novel, flexible approach toward
the photocatalytic synthesis of a wide range of vicinal
heteroatom arrays. Indeed, the use of ureas in place of
carbamates affords the products of net alkene diamination
(Scheme 4b). The optimal photocatalyst (MesAcrMe+) and
oxidant [Cu(OAc)2] were slightly different in this case, which
demonstrates that these variables can be tuned to achieve
optimal reactivity in different transformations. Moreover, the
irradiation of dihydronaphthalene with various alcohols in the
presence of Cu(TFA)2 and TPPT results in alkene dioxygen-
ation (Scheme 4c). Thus, these preliminary results indicate
that the identity of each of the heteroatoms introduced across
the alkene can be varied and suggest that this reaction design
plan might be generalizable to a much wider range of oxidative
functionalization reactions.
In summary, copper(II) salts are effective oxidants that
enable the oxidative difunctionalization of alkenes using photo-
redox catalysis. More broadly, these results are exciting because
organoradical intermediates are common in photoredox reac-
tions. The ability to divert these intermediates toward cationic
reactivity using convenient Cu(II) oxidants suggests a powerful
and conceptually novel approach toward the design of a wide
range of new oxidative functionalization reactions. Studies
toward this broader goal are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03345.
̈
Hormann, F. M.; Bach, T. Iminium and enamine catalysis in
Experimental procedures and characterization data
(PDF)
enantioselective photochemical reactions. Chem. Soc. Rev. 2018, 47,
278−290. (f) Silvi, M.; Melchiorre, P. Enhancing the potential of
enantioselective organocatalysis with light. Nature 2018, 554, 41−49.
AUTHOR INFORMATION
́
(4) (a) Rueda-Becerril, M.; Mahe, O.; Drouin, M.; Majewski, M. B.;
■
West, J. G.; Wolf, M. O.; Sammis, G. M.; Paquin, J. F. Direct C-F
bond formation using photoredox catalysis. J. Am. Chem. Soc. 2014,
136, 2637−2641. (b) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W.
C. Decarboxylative Fluorination of Aliphatic Carboxylic Acids via
Photoredox Catalysis. J. Am. Chem. Soc. 2015, 137, 5654−5657.
(c) Griffin, J. D.; Cavanaugh, C. L.; Nicewicz, D. A. Reversing the
Regioselectivity of Halofunctionalization Reactions through Cooper-
ative Photoredox and Copper Catalysis. Angew. Chem., Int. Ed. 2017,
56, 2097−2100. (d) Davies, J.; Sheikh, N. S.; Leonori, D. Photoredox
Imino Functionalizations of Olefins. Angew. Chem., Int. Ed. 2017, 56,
13361−13365.
Corresponding Author
*E-mail: tyoon@chem.wisc.edu.
ORCID
Tehshik P. Yoon: 0000-0002-3934-4973
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the NIH (GM098886). The mass
spectroscopy facilities at UWMadison are funded in part
by the NIH (S10 OD020022) as are the NMR facilities
(S10 OD012245).
(5) (a) Allen, L. J.; Cabrera, P. J.; Lee, M.; Sanford, M. S. N-
Acyloxyphthalimides as Nitrogen Radical Precursors in the Visible
Light Photocatalyzed Room Temperature C−H Amination of Arenes
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(b) Greulich, T. W.; Daniliuc, C. G.; Studer, A. N-Aminopyridinium
Salts as Precursors for N-Centered Radicals − Direct Amidation of
Arenes and Heteroarenes. Org. Lett. 2015, 17, 254−257. (c) Brachet,
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