Tandem copper and photoredox catalysis in photocatalytic alkene difunctionalization reactions

Article abstract of DOI:10.3762/bjoc.15.30

Oxidative alkene difunctionalization reactions are important in synthetic organic chemistry because they can install polar functional groups onto simple non-polar alkene moieties. Many of the most common methods for these reactions rely upon the reactivity of pre-oxidized electrophilic heteroatom donors that can often be unstable, explosive, or difficult to handle. Herein, we describe a method for alkene oxyamination and diamination that utilizes simple carbamate and urea groups as nucleophilic heteroatom donors. This method uses a tandem copper–photoredox catalyst system that is operationally convenient. The identity of the terminal oxidant is critical in these studies. Ag(I) salts proved to be unique in their ability to turn over the copper cocatalyst without deleteriously impacting the reactivity of the organoradical intermediates.

Full text of DOI:10.3762/bjoc.15.30

Tandem copper and photoredox catalysis in photocatalytic
alkene difunctionalization reactions
Nicholas L. Reed, Madeline I. Herman, Vladimir P. Miltchev and Tehshik P. Yoon*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 351–356.
Department of Chemistry, University of Wisconsin–Madison, 1101
University Avenue, Madison, Wisconsin 53706, United States
doi:10.3762/bjoc.15.30
Received: 13 November 2018
Accepted: 22 January 2019
Published: 05 February 2019
Email:
Tehshik P. Yoon* - tyoon@chem.wisc.edu
*
Corresponding author
This article is part of the thematic issue "Reactive intermediates part I:
radicals".
Keywords:
copper; diamination; oxidative functionalization; oxyamination;
photoredox catalysis; radical
Associate Editor: C. Stephenson
©
2019 Reed et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Oxidative alkene difunctionalization reactions are important in synthetic organic chemistry because they can install polar func-
tional groups onto simple non-polar alkene moieties. Many of the most common methods for these reactions rely upon the reactivi-
ty of pre-oxidized electrophilic heteroatom donors that can often be unstable, explosive, or difficult to handle. Herein, we describe a
method for alkene oxyamination and diamination that utilizes simple carbamate and urea groups as nucleophilic heteroatom donors.
This method uses a tandem copper–photoredox catalyst system that is operationally convenient. The identity of the terminal oxidant
is critical in these studies. Ag(I) salts proved to be unique in their ability to turn over the copper cocatalyst without deleteriously
impacting the reactivity of the organoradical intermediates.
Introduction
Over the past decade, a renewed interest in synthetic photo- been productively utilized in asymmetric transformations [7-9],
chemistry has resulted in the discovery of a broad range of pow- cross-couplings [10-12], and oxidative decarboxylation reac-
erful new bond-forming transformations [1-4]. Much of this tions [13,14], among others. The use of a cocatalyst to control
work has been premised on the ability of visible light-activated these photochemical transformations enables reactions that are
photocatalysts to generate highly reactive odd-electron interme- not accessible from the native reactivity of the organoradical
diates via photoinduced electron transfer processes. A major intermediates by themselves.
theme of research that has emerged from these studies is the ap-
plication of various cocatalysts to intercept the organoradical Our laboratory is interested in the design of photochemical
intermediates of photoredox reactions and modulate their subse- strategies for oxidative functionalization reactions [15,16]. We
quent reactivity [5,6]. The combination of photoredox catalysis recently described [17] a new approach to alkene difunctional-
with transition metals, Lewis acids, and organocatalysts has ization that combines the photoredox activation of electron-rich
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Beilstein J. Org. Chem. 2019, 15, 351–356.
alkenes with copper(II)-mediated oxidation of electron-rich can be observed precipitating from solution over the course of
radicals as described by Kochi [18-20]. These studies resulted the reaction.
in the development of a general new protocol for oxyamination
(
Figure 1a) and diamination (Figure 1b) of alkenes. The mecha- Copper(II) salts have been demonstrated to be convenient termi-
nism we have proposed for photocatalytic oxyamination is nal oxidants in a variety of synthetically useful catalytic reac-
outlined in Figure 1c. Photoinduced one-electron oxidation of tions [23-26]. They are easily handled, are available from
an appropriately electron-rich styrene 1 results in the formation commodity chemicals for nominal cost, and present minimal
of a radical cation 1•+ that is susceptible to attack by various environmental and health concerns in large-scale applications.
heteroatomic nucleophiles, including carbamates [21,22]. The use of stoichiometric copper(II) reagents, however, could
Subsequent oxidation of radical 7 by Cu(II) affords a formally become prohibitive in certain applications where specific, syn-
cationic intermediate that is trapped by the carbamoyl oxygen to thetically laborious ligand sets might be required, as in enantio-
afford oxonium 8. The loss of the tert-butyl cation provides the selective catalytic oxidation reactions or certain cross-coupling
oxyamination product 2, which can be isolated in good yields applications. We wondered, therefore, if catalytic loadings of
with excellent diastereoselectivity. Turnover of the photocata- copper(II) salts might be used in these reactions by adding a
lyst can be coupled to the reduction of Cu(I) to Cu(0), which secondary terminal oxidant to turn over the intermediate
Figure 1: a) Photocatalytic oxyamination, b) photocatalytic diamination, and c) proposed mechanism for photocatalytic oxyamination using copper(II)
as a terminal oxidant.
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Beilstein J. Org. Chem. 2019, 15, 351–356.
copper(I) complex. We describe herein the results of this inves- radical intermediates, would not generate any highly reactive
tigation, which has led to the identification of a tandem oxygen species, and would not produce toxic or chromatograph-
photoredox copper(II) catalytic system for the net-oxidative ically problematic byproducts.
difunctionalization of alkenes.
As a starting point for our optimization studies, we examined
Results and Discussion
the intramolecular oxyamination of carbamate 1 (Table 1), a
A range of mild oxidants can oxidize copper(I) to copper(II), reaction we had previously studied under stoichiometric Cu(II)
and the use of dioxygen for this purpose is frequently exploited conditions and found to proceed in good yield using 2.5 mol %
to effect synthetically useful copper-catalyzed aerobic oxida- 2,4,6-triphenylpyrylium tetrafluoroborate (TPPT, 3) as a photo-
tion reactions [27,28]. However, the use of molecular oxygen as catalyst and 1.2 equiv of Cu(TFA)2 as a stoichiometric oxidant.
a terminal oxidant presents unique challenges in photoredox We lowered the loading of Cu(TFA)2 to 10 mol % and assessed
chemistry. Triplet dioxygen rapidly quenches the excited state the effect of a series of alternate oxidants that have been used in
of most common photoredox catalysts [29-31], decreasing their other copper-catalyzed oxidation reactions. Most failed to
effective lifetimes and producing singlet dioxygen or super- produce significant quantities of the desired product (Table 1,
oxide, which can react destructively with many common entries 1–3). As expected, the use of oxygen as a terminal
organic functional groups. Moreover, the organoradical inter- oxidant resulted in rapid conversion of 1 to an intractable mix-
mediates that characterize much of photoredox chemistry can ture of decomposition products, with only trace formation of the
react rapidly with ground-state dioxygen to afford unstable desired oxyamination product (Table 1, entry 1). Other oxidants
hydroperoxy radicals that can also decompose unproductively afforded less decomposition but were not effective in turning
[
32,33]. Indeed, in our previous study of photocatalytic alkene over the Cu(II) cocatalyst (Table 1, entries 2 and 3). Of all of
difunctionalization, we found that dioxygen and similar com- the oxidants screened, silver(I) salts were found to be uniquely
monly used terminal oxidants resulted in unproductive decom- effective at mediating turnover of the copper(II) catalyst
position of the substrates [17], and that Cu(II) oxidants were [34-36]. After screening commercially available silver(I) salts,
uniquely suitable in this application. At the outset of this inves- Ag2CO3 was found to be the optimal terminal oxidant (Table 1,
tigation, therefore, we imagined that the identification of a entry 5). There is a competitive silver-mediated photodecompo-
co-oxidant for use with catalytic Cu(II) might face similar prac- sition process that consumes the starting alkene unproductively,
tical constraints. Ideally, we hoped to identify a terminal and thus the copper(II)/silver(I) ratio was tuned to optimize the
oxidant that would be compatible with the chemistry of the efficiency of the desired oxyamination process (Table 1, entries
Table 1: Optimization of dual-catalytic reaction conditionsa.
entry
Cu(TFA)2 (mol %)
oxidant
yieldb
1
2
3
4
5
6
7
8
9
10
10
10
10
10
30
30
0
air
8%
trace
9%
K2S2O8 (3 equiv)
MnO2 (3 equiv)
Ag2O (3 equiv)
Ag2CO3 (3 equiv)
Ag2CO3 (3 equiv)
Ag2CO3 (1 equiv)
Ag2CO3 (1 equiv)
none
25%
43%
54%
70%
7%
30
30
30
10%
3%
10c
1d
Ag2CO3 (1 equiv)
Ag2CO3 (1 equiv)
1
trace
aAll reactions were conducted in degassed CH2Cl2 and irradiated with a 15 W blue LED flood lamp for 2 h. bYields were determined by 1H NMR anal-
ysis of the unpurified reaction mixtures using phenanthrene as an internal standard. cNo TPPT. dNo light.
353

Beilstein J. Org. Chem. 2019, 15, 351–356.
5
3
–7). Optimal conditions were found to be 2.5 mol % TPPT,
0 mol % Cu(TFA)2, and 1 equiv Ag2CO3 in CH2Cl2 (Table 1,
entry 7). Finally, control experiments validated the necessity of
each reaction component. Minimal product formation was ob-
served when Cu(TFA)2, Ag2CO3, TPPT, or light were omitted
from the reaction (Table 1, entries 8–11), confirming that the
combination of photoredox and copper(II) catalysis is critical to
achieve good reactivity.
We found that these optimized reaction conditions are applic-
able to both oxyamination and diamination reactions. Experi-
ments probing the scope of these transformations are summa-
rized in Figure 2. A range of styrenes bearing varying electron-
donating and electron-withdrawing substituents smoothly
undergo oxyamination (9–12), as do ortho-substituted styrenes
(
13). The presence of an electron-rich heterocycle is also toler-
ated (14), without any evidence of oxidative decomposition of
this sensitive functional group. Modifications to the alkyl tether
(
15) did not adversely affect the reaction. Intermolecular
oxyamination of styrenes is also feasible using these conditions.
While simple styrenes polymerize rapidly under these condi-
tions, a range of β-substituted styrenes undergo smooth oxyami-
nation using tert-butyl carbamate as the nucleophilic nitrogen
atom source (16–18). Finally, alkene diamination is also readily
achieved using N-phenylureas as nucleophiles, although acri-
dinium photocatalyst 6 afforded modestly higher yields in these
reactions (19–21).
A complete mechanistic picture of this reaction will require ad-
ditional experimentation; however, control experiments demon-
strate that Ag2CO3 is not a competent terminal oxidant on its
own (Table 1, entry 9) and that the presence of Cu(II) is critical
for the oxyamination to occur (Table 1, entry 8). Moreover, our
previous studies demonstrated that Cu(II) can serve as a compe-
tent terminal oxidant in a stoichiometric fashion. Thus, it seems
clear that the role of the Ag(I) additive in this reaction is to
re-oxidize Cu(I) to Cu(II), and that the Cu(II) salt in this trans-
formation is indeed a cocatalyst for the oxidative difunctional-
ization of styrenes. Efforts to render this transformation enan-
tioselective by utilizing chiral Cu(II) complexes have thus far
Figure 2: Scope studies for dual-catalytic alkene difunctionalization
using 2.5 mol % 3, 30 mol % Cu(TFA)2, and a 15 W blue flood lamp.
Diastereomer ratios >20:1 unless otherwise noted. a3:1 dr. b10:1 dr.
cReaction conducted using MesAcrMe+ (6) as photocatalyst.
not been successful. A screen of several classes of privileged ondary terminal oxidant, and that Ag(I) salts appear to be
ligands for asymmetric copper catalysis produced only racemic uniquely effective in this capacity. This work thus provides a
oxyamination products. We interpret this observation as an indi- platform for the development of enantioselective photocatalytic
cation that Cu(II) is unable to control the stereochemistry of the alkene difunctionalization reactions that can use a chiral Cu(II)
C–N bond-forming step, as one might expect from its proposed complex as a substoichiometric catalyst rather than as a termi-
role in radical oxidation (Figure 1C).
nal oxidant. Moreover, much of the utility of photoredox cataly-
sis has been predicated on its ability to generate radical interme-
diates under mild and operationally convenient conditions. The
Conclusion
These studies have demonstrated that the copper-mediated ability to intercept transient photogenerated organoradical inter-
alkene difunctionalization reactions recently reported by our mediates and divert them towards carbocation reactivity is an
laboratory can be rendered catalytic in Cu(II) by adding a sec- intriguing paradigm for the expansion of photoredox chemistry
354

Beilstein J. Org. Chem. 2019, 15, 351–356.
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Madeline I. Herman - https://orcid.org/0000-0003-1156-2968
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