Organophotocatalytic Generation of N- and O-Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes

Article abstract of DOI:10.1002/chem.201602597

A cooperative TEMPO and photoredox catalytic strategy was applied for the first time to the direct conversion of N?H and O?H bonds into N- and O-centred radicals, enabling a general and selective oxidative radical oxyamination and dioxygenation of various

Full text of DOI:10.1002/chem.201602597

A Journal of
Accepted Article
Title: Organophotocatalytic Generation of N- and O-Centred Radicals Enable Aero-
bic Oxyamination and Dioxygenation of Alkenes
Authors: Wen-JIng Xiao; Xiao-Qiang Hu; Jun Chen; Jia-Rong Chen; Dong-Mei Yan
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201602597
Link to VoR: http://dx.doi.org/10.1002/chem.201602597
Supported by

Chemistry - A European Journal
10.1002/chem.201602597
COMMUNICATION
Organophotocatalytic Generation of N- and O-Centred Radicals
Enable Aerobic Oxyamination and Dioxygenation of Alkenes
Xiao-Qiang Hu, Jun Chen, Jia-Rong Chen,* Dong-Mei Yan, and Wen-Jing Xiao
Abstract: A cooperative TEMPO and photoredox catalytic strategy
was applied for the first time to the direct conversion of N-H and O-H
bonds into N- and O-centred radicals, enabling a general and
selective oxidative radical oxyamination and dioxygenation of
various β,γ-unsaturated hydrazones and oximes. In the reaction, O2
was employed not only as a terminal oxidant but also as the oxygen
source. This protocol provides efficient access to the synthesis of
various synthetically and biologically important pyrazoline, pyridazine
and isoxazoline derivatives under metal-free and mild reaction
conditions. Mechanistic studies revealed that the cooperative
organophotocatalytic system functions via two single-electron
transfer (SET) processes.
MacMillan,[10a] Sanford[10b] and others[10c-f] have demonstrated
that the incorporation of a photolabile moiety into the amine
substrates enable photocatalytic formation of N-centred radicals
b]
and the subsequent C-N bond formation. We[11a,
and
Knowles[11c] have independently reported that visible-light
photocatalysis enabled the recalcitrant N-H bonds to be directly
converted into N-centred radicals via oxidative deprotonation
electron transfer (ODET) or concerted proton-coupled electron
transfer (PCET) activation, respectively. Quite recently, Chen
and co-workers reported the first example of the generation of
important alkoxyl radicals by photocatalytic cleavage of the pre-
formed N-O bond or the in-situ-derived I-O bond.[12] Most of
these reactions rely on the use of a single photocatalyst or N-
and O-functionalized precursors, limiting the substrate scope
owing either to the inherent oxidation state of the photocatalyst
or to the tedious preparative procedure of the substrates. To our
knowledge, no general and efficient catalytic systems have been
developed for the direct conversion of N-H and O-H bonds into
N- or O-centred radicals and the application of these reactive
species to radical oxyamination and dioxygenation of alkenes.[13]
Cooperative catalysis that involves two distinct catalytic
entities in a transformation is currently a major focus of research
in the field of catalytic science.[1] Application of this strategy can
often enable otherwise inaccessible catalytic reactivity modes. In
the last decade, visible-light photoredox catalysis and
organocatalysis have developed into two new essential
branches of catalysis because of their unique and mild activation
modes.[2,3] Given their high functional group compatibility, the
combination of these two catalytic strategies has recently been
demonstrated to be a powerful platform for new reaction
development and selectivity control.[4] Employing this
cooperative catalytic mode, significant advances have thus been
achieved. Elegant examples include highly efficient and
stereoselective radical functionalization of various carbonyl
compounds,[5] tertiary amines,[6] and alkenes[7]. Despite these
important advances, development of general, efficient and
conceptually new cooperative organophotocatalytic systems to
activate relatively inactive chemical bonds and engineer new
chemical transformations remains an important but challenging
task.
In recent years, visible-light photocatalytic alkene
difunctionalization reactions have been established as an
efficient and mild approach for the construction of various C-C or
C−X (X = heteroatom or halogen) bonds.[8] In this context, the
photocatalytic N- or O-centred radical-mediated oxidative
oxyamination and dioxygenation of alkenes remain largely
unexplored because of the limited methods for their efficient
generation.[9] The seminal studies by the groups of
Scheme 1. Reaction design: oxidative radical oxyamination and dioxygenation
of unactivated alkenes by cooperative TEMPO and photoredox catalysis.
TEMPO, 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl, is a well-
known and stable nitroxyl radical with wide applications in
radical trapping and hydrogen atom transfer (HAT) processes;
and its oxoammonium salt has also been widely exploited as a
catalytic or stoichiometric cooxidant in transition-metal-mediated
transformations.[14] However, very few examples of the use of
TEMPO as a single-electron transfer (SET) cocatalyst in visible-
light-induced photocatalysis have been reported. In 2015,
Nicewicz and co-workers developed an elegant TEMPO and
acridinium photooxidant-based dual catalytic system for site-
selective aryl C-H amination reactions, where TEMPO served as
an HAT catalyst (Scheme 1a).[15] Very recently, Chen’s group
exploited TEMPO as a redox mediator and achieved a visible-
light-induced ARS-sensitized TiO2-catalysed heterogeneous
oxidation of organic sulphides.[16] Inspired by these works and
[]
X.-Q. Hu, J. Chen, Prof. Dr. J.-R. Chen, D.-M. Yan, Prof. Dr. W.-J.
Xiao
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide
& Chemical Biology, Ministry of Education, College of Chemistry
Central China Normal University (CCNU)
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: chenjiarong@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/
Prof. Dr. W.-J. Xiao
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin 300072 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.

Chemistry - A European Journal
10.1002/chem.201602597
COMMUNICATION
irradiation by 7 W blue LEDs (450-460 nm); PPh3 (0.2 mmol, 1.0 equiv) was
then added, and the mixture was stirred for another 10 min. [b] Yield of the
isolated product. [c] Without photocatalyst. [d] Without TEMPO. [e] Without
light. [f] Without O2 balloon. [g] Without K2CO3. PC-I: 9-Mesityl-10-
based on our ongoing programme of research on visible-light-
induced dual catalysis,[17] we envisaged that
a suitable
cooperative TEMPO/photocatalytic system would likely provide a
new method for N- and O-centred radical-mediated
difunctionalization of alkenes, where molecular oxygen (O2) is
used as a green terminal oxidant and oxygen source.[18] Herein,
we present the implementation of this blueprint and its
application to the radical oxyamination and dioxygenation of β,γ-
unsaturated hydrazones and oximes (Scheme 1b).
.
methylacridinium perchlorate. PC-II: Ru(bpy)3Cl2 6H2O. TEMPO: 2,2,6,6-
tetramethylpiperidine-N-oxyl.
Table 2: Substrate scope of the cooperative TEMPO/photocatalytic oxidative
radical oxyamination of β,γ-unsaturated hydrazones.[a, b]
In our initial screening for reactivity, we selected the readily
accessible β,γ-unsaturated hydrazone 1a as the model substrate
and examined the combination of a photocatalyst, 9-mesityl-10-
methylacridinium perchlorate (PC-I) (5 mol%),[19] and TEMPO (5
mol%) under a balloon of O2 by irradiation with 7 W blue LEDs.
To our delight, the reaction proceeded smoothly to give the
hydroxyamination product 2a upon subsequent treatment with
PPh3; an increase of TEMPO loading (20 mol%) substantially
improved the yield from 30% to 83% (entries 1-3). A further brief
investigation of reaction parameters such as the reaction
medium, base and photocatalyst gave the optimal conditions:
the combination of 5 mol% of PC-1 and 20 mol% of TEMPO as
the cooperative organophotocatalytic system, 1.5 equivalents of
K2CO3 as the base, in CH3CN at room temperature, giving an
85% yield of 2a (entry 4).[20] To verify the necessity for each
component involved in this reaction, we performed a series of
control experiments on 1a (Table 1, entries 6-9). The results
clearly revealed that the photocatalyst, TEMPO, visible light, and
O2 were all critical to the reaction. Interestingly, although K2CO3
was not required for the model reaction (entry 10), subsequent
studies of the substrate scope showed that the addition of
stoichiometric K2CO3 obviously improved the yield, especially in
the case of substrates with electron-withdrawing substituents.[20]
Table 1: Optimization of the cooperative TEMPO/photocatalytic oxidative
radical oxyamination of β,γ-unsaturated hydrazones.[a]
Entry
Cat.
Solvent
Base
x
Yield [%][b]
1
PC-I
PC-I
PC-I
PC-I
PC-II
_
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
NaHCO3
NaHCO3
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
_
5
30
56
83
85
83
0
2
10
20
20
20
20
_
[a] For 2a-u, reactions were performed with 1 (0.3 mmol), K2CO3 (0.45 mmol),
PC-I (5 mol%), TEMPO (20 mol%), and O2 balloon in CH3CN (6.0 mL) at room
temperature for 5-12 h under the irradiation by 7 W blue LEDs (450-460 nm);
PPh3 (0.3 mmol, 1.0 equiv) was then added and the mixture was stirred for
another 10 min; for 3a-h, TEMPO (10 mol%). [b] Yield of the isolated product.
3
4
5
6[c]
7[d]
8[e]
9[f]
10[g]
We then investigated the substrate scope of this
photocatalytic oxidative radical oxyamination by using a range of
diversely substituted β,γ-unsaturated hydrazones. As shown in
Table 2, the electronic properties and substitution patterns of the
aromatic ring of β,γ-unsaturated hydrazones did not obviously
influence the reaction efficiency. The hydrazones 1a-h bearing
electron-withdrawing (Cl, Br, CF3) or electron-donating
substituents (Me, MeO) at the para- or meta-position of the
PC-I
PC-I
PC-I
PC-I
32
0
20
20
20
0
86
[a] Reaction conditions: 1a (0.20 mmol), photocatalyst (5.0 mol%), TEMPO (20
mol%), O2 balloon, solvent (4.0 mL) at room temperature for 5 h under

Chemistry - A European Journal
10.1002/chem.201602597
COMMUNICATION
was then added and the mixture was stirred for another 10 min. [b] Yield of the
isolated product.
phenyl ring underwent the desired reaction smoothly, giving the
expected products 2a-h in 67-91% yield. Moreover, a range of
hydrazones 1i-k with linear or branched aliphatic moieties also
proved to be suitable for this reaction, with the products 2i-k
formed in 51-73% yield. Encouraged by these results, we
continued to investigate the variation of the alkene moiety. As
expected, the hydrazone 1l bearing a methyl substituent at the
2-position of alkene could also undergo the oxyamination
reaction efficiently to deliver the product 2l in 76% yield. The
reaction of hydrazone 1m with an internal alkene also
proceeded smoothly to furnish a 54% yield of 2m. Notably, this
protocol could to be successfully extended to diversely
substituted β,γ-unsaturated hydrazones with geminal methyl
groups at the α-position. For example, a wide range of
hydrazones 1n-t bearing aromatic, heteroaromatic, and aliphatic
functional groups were all well tolerated, and the corresponding
products 2n-t were obtained with 73-93% yield. Moreover,
replacement of the Ts protecting group of nitrogen by Ms group
also furnished the corresponding product 2u in 63% yield.
Oxygen radicals are another important class of reactive
intermediates with broad applications in both biological
processes and organic transformations. The direct cleavage of
the O-H bond for their generation is an attractive but
thermodynamically challenging pathway.[22] Gratifyingly, our mild
catalytic system allowed for a series of diversely substituted β,γ-
unsaturated oximes to undergo efficient O-radical-mediated 5-
exo oxidative radical dioxygenation reactions (Table 3). An array
of electronically diverse phenyl rings with electron-donating or
electron-withdrawing groups at the para- or meta-position and a
heteroaryl group were all well tolerated, delivering products 5a-g
in 60-97% yield. Once again, similar to the alkene moiety,
substrates with 2-methyl-substituted alkene (4h) or internal
alkenes (4i and 4j) also proved to be suitable for this
transformation, conferring the corresponding products 5h-j in
satisfactory yields (65-78%).
Notably, this protocol represents the first example of visible
light photocatalytic radical dioxygenation of oximes without any
transition-metal catalyst,[23a] stoichiometric radical initiator or
oxidant.[13a,23b] Thus, this reaction provides an economical and
mild alternative access pathway to diverse synthetically useful
isoxazoline derivatives.
Employing this cooperative organophotocatalytic strategy, we
further attempted a 6-endo oxidative radical oxyamination of β,γ-
unsaturated hydrazones by introducing an aryl group into the 2-
position of the alkene. According to our previous DFT calculation
studies on the cyclization of hydrazonyl radicals across the
alkene,[11b] the regioselectivity of the hydrazonyl radicals was
highly dependent on the substitution patterns of the alkene
moiety. The incorporation of an aryl group into the 2-position of
alkene could stabilize the newly generated benzyl radical
intermediate, thus leading to a 6-endo radical cyclization
process. Indeed, the reactions of a wide variety of aryl and
aliphatic hydrazones with diverse electronic or steric
characteristics proceeded efficiently to produce the biologically
important pyridazine derivatives 3a-h in generally high yields
(59-91%), highlighting the synthetic potential of this protocol.
The structures of 2n and 3a were also unambiguously
determined by X-ray crystallographic analysis.[21]
Table 3: Substrate scope of TEMPO/photocatalytic oxidative radical
dioxygenation of β,γ-unsaturated oximes.[a, b]
Scheme 2. Mechanistic studies.
To gain some insight into the possible reaction mechanism,
a series of control experiments were then carried out using 1a
(Scheme 2). First, we observed that the use of 20 mol% of
TEMPOnium-BF4 6 under the otherwise identical conditions
produced results comparable to those obtained using TEMPO,
with 2a being isolated in 76% yield (Scheme 2a). In the absence
of the photocatalyst and visible light, the addition of 20 mol% of
6 only gave a 21% yield of 2a, whereas a stoichiometric amount
of 6 resulted in complete conversion of substrate 1a, furnishing a
mixture of 2a and TEMPO-adduct 7 in 38% and 41% yield,
respectively (Scheme 2b). These results suggest that TEMPO
may be initially oxidized by the photoexcited PC-1* into TEMPO+
species that then serve as the reactive SET oxidant. The half-
[a] Reactions were performed with 4 (0.3 mmol), PC-I (5 mol%), TEMPO (10
mol%), and O2 balloon in CH3CN (6.0 mL) at room temperature for 12-24 h
under irradiation by 7 W blue LEDs (450-460 nm); PPh3 (0.3 mmol, 1.0 equiv)

Chemistry - A European Journal
10.1002/chem.201602597
COMMUNICATION
another SET oxidation of the nitrogen anion A, generated from
substrate 1a via deprotonation, by the highly oxidizing TEMPO+
gives rise to the key N-centred radical intermediate B, together
with the regeneration of TEMPO to close the organocatalytic
cycle. A 5-exo radical cyclization of N-radical B gives rise to C-
centred radical C (Scheme 3a, Path A) that could be easily
trapped by O2 to afford alkylhydroperoxy radical D.[25] Then, the
intermediate D undergoes a sequential SET reduction and
protonation to give alkylhydroperoxide 8. Finally, reduction of
alkylhydroperoxide 8 by PPh3 furnishes the target product 2a.
The reduced photocatalyst PC-I1- species can be oxidized by O2
or hydroperoxy radical D to regenerate the ground state
photocatalyst PC-I and finish the photocatalytic cycle. It should
be noted that a 6-endo cyclization of N-centred radical B’ would
be a predominant pathway when R3 is aryl group due to the
stability of the newly generated benzyl radical intermediate C’
(Scheme 3b, Path b). Then, the intermediate C’ undergoes a
same sequential SET reduction and protonation process to give
the desired six-membered ring product 3. In addition, the
mechanistic studies indicated that the the oxidative
dioxygenation of oximes proceeded by a same pathway. [20]
To demonstrate the synthetic potential of our newly
developed method, we also carried out a gram-scale reaction of
1a. The reaction still proceeded efficiently, and product 2a was
isolated in 76% yield.[20] Moreover, the hydroxyl group of 2a was
easily transformed into a synthetically valuable azido group via
two routine elaborations, giving the product 9 in 90% yield
wave redox potential of TEMPO (E1/2 = +0.62 V vs. Ag/AgCl)
also points to this possibility.[15,24] To verify the origin of the
oxygen atom in the final product, we performed 18O2-labelling
experiments with 1a under an 18O2 atmosphere (Scheme 2c). As
expected, the 18O-labeled product 18O-2a was obtained in 56%
yield under the standard conditions, suggesting that O2 indeed
participated in the reaction and was incorporated into the final
products. Notably, we observed that alkylhydroperoxide 8 was
successfully isolated in 67% yield when NaHCO3 was used as
the base and that it was further easily transformed into 2a with
95% yield upon treatment with PPh3, indicating that
alkylhydroperoxide
8
was the key intermediate in the
oxyamination reaction (Scheme 2d).
To gain greater insight into the photoredox catalytic cycle, we
performed a series of emission quenching experiments. The
results indicated that the photoexcited PC-1* was more
efficiently quenched by TEMPO than substrates 1a and 4a.
Additionally, the photoexcited PC-1* was quenched more rapidly
by 1a under basic conditions than in the absence of a base.
These observations are consistent with the fact that the addition
of a catalytic amount of TEMPO and stoichiometric K2CO3 can
substantially accelerate the reaction and improve the yield.
Moreover, the results of on-off light experiments implied that the
radical chain process is not the predominant pathway in this
transformation, although it cannot be completely ruled out at the
current stage.[20]
(Scheme
4).
The
azide
9
underwent
a
further
reduction/protection sequence to furnish the important
compound 10 with 68% yield.[26]
Scheme 4. Synthetic transformations.
In conclusion, we developed
a cooperative TEMPO/
photocatalytic system for direct conversion of N-H and O-H
bonds into N- and O-centred radicals, enabling a general and
selective oxidative radical oxyamination and dioxygenation of
β,γ-unsaturated hydrazones and oximes. In this protocol, O2 was
employed not only as the sole terminal oxidant but also as the
oxygen source. As such, the O2 was incorporated into a wide
range of synthetically and biologically important pyrazoline,
pyridazine and isoxazoline derivatives with generally high yields
under mild and metal-free conditions. Furthermore, detailed
control experiments were conducted to elucidate the cooperative
catalytic mode. Further intensive study and application of this
cooperative organophotocatalytic system is currently underway.
Scheme 3. Proposed mechanism.
On the basis of the aforementioned experimental results, it
seems that current reactions proceed through a pathway that
appears to be distinct from our previously developed single
photocatalyst-mediated hydroamination.[11a,b] Thus, a cooperative
organophotocatalytic mode that functions via two single-electron
transfer (SET) processes is proposed as shown in Scheme 3a.
First, photoexcitation of the photocatalyst PC-I generates the
excited-state PC-I* species via irradiation by 7 W blue LEDs.
The excited-state photocatalyst PC-I* (Eox1/2 = +2.06 V)[13] then
serves as an 1e-oxidant to oxidize TEMPO (E1/2 = +0.62 V) into
its highly oxidizing state, TEMPO+, via an SET process,[24] with
the release of the reduced photocatalyst PC-I1-. Subsequently,
Experimental Section
1a (94.2 mg, 0.3 mmol), PC-I (5 mol%), K2CO3 (62.2 mg, 0.45
mmol) and TEMPO (20 mol%) were dissolved in CH3CN (6.0
mL) with a O2 balloon. After that, the solution was stirred at a
distance of ~5 cm from a 7 W blue LEDs (450-460 nm) at room
temperature until the reaction was completed. Then, Ph3P (1.0
eq.) was added to the mixture and the mixture was stirred at

Chemistry - A European Journal
10.1002/chem.201602597
COMMUNICATION
2015, 127, 4127-4131; Angew. Chem. Int. Ed. 2015, 54, 4055-4059; f)
K. Miyazawa, T. Koike, M. Akita, Chem. Eur. J. 2015, 21, 11677-11680.
[11] a) X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M. Beauchemin,
W.-J. Xiao, Angew. Chem. 2014, 126, 12359-12363; Angew. Chem. Int.
Ed. 2014, 53, 12163-12167; b) X.-Q. Hu, X. Q, J.-R. Chen, Q. Wei, Q.-
Q. Zhao, Y. Lan, W.-J. Xiao, Nat. Commun. 2016, 7:11188, doi:
10.1038/ncomms11188; c) G. J. Choi, R. R. Knowles, J. Am. Chem.
Soc. 2015, 137, 9226-9229; For electrochemical generation of amidyl
radicals from N-H bonds, see: d) L. Zhu, P. Xiong, Z. Y. Mao, Y. H.
Wang, X. Yan, X. Lu, H.-C. Xu, Angew. Chem. 2016, 128, 2266-2269;
Angew. Chem. Int. Ed. 2016, 55, 2226-2229; e) F. Xu, L. Zhu, S. Zhu, X.
Yan, H.-C. Xu, Chem. Eur. J. 2014, 20, 12740-12744.
room temperature for another 10 min. The crude product was
purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate 10:1~2:1).
Acknowledgements
We are grateful to the NSFC (No. 21272087, 21472058, and
21232003), the Youth Chen-Guang Project of Wuhan (No.
2015070404010180), and CCNU (No. CCNU15A02009) for
support of this research. X.-Q.H. thanks the Excellent Doctorial
Dissertation Cultivation Grant from CCNU (No. 2015YBZD011).
[12] a) J. Zhang, Y. Li, F. Zhang, C. Hu, Y. Chen, Angew. Chem. 2016, 128,
1904-1907; Angew. Chem. Int. Ed. 2016, 55, 1872-1875; b) K. Jia, F.
Zhang, H. Huang, Y. Chen, J. Am. Chem. Soc. 2016, 138, 1514-1517.
[13] For selected examples of stoichiometric oxidant-mediated or copper-
catalysed generation of N-radicals, see: a) B. Han, X. L. Yang, R. Fang,
W. Yu, C. Wang, X. Y. Duan, S. Liu, Angew. Chem. 2012, 124, 8946-
8950; Angew. Chem. Int. Ed. 2012, 51, 8816-8820; b) X.-Y. Duan, N.-N.
Zhou, R. Fang, X.-L. Yang, W. Yu, B. Han, Angew. Chem. 2014, 126,
3222-3226; Angew. Chem. Int. Ed. 2014, 53, 3158-3162; c) M.-K. Zhu,
Y.-C. Chen, T.-P. Loh, Chem. Eur. J. 2013, 19, 5250-5254; d) Y. F.
Wang, H. Chen, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134,
11980-11983.
Keywords: organophotocatalysis • N-centred radical • O-
centred radical • hydrazones • oximes
[1]
For selected reviews, see: a) A. E. Allen, D. W. Macmillan, Chem. Sci.
2012, 3, 633-658; b) Z. Du, Z. Shao, Chem. Soc. Rev. 2013, 42, 1337-
1378; c) D.-F. Chen, Z.-Y. Han, X.-L. Zhou, L.-Z. Gong, Acc. Chem.
Res. 2014, 47, 2365-2377.
[2]
[3]
R. Rios Torres, Ed., Stereoselective Organocatalysis: Bond Formation
Methodologies and Activation Modes, Wiley-VCH: Weinheim, 2013.
For recent reviews on visible light photocatalysis, see: a) J. Xuan, W.-J.
Xiao, Angew. Chem. 2012, 124, 6934-6944; Angew. Chem. Int. Ed.
2012, 51, 6828-6838; b) L. Shi, W.-J. Xia, Chem. Soc. Rev. 2012, 41,
7687-7697; c) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem.
Rev. 2013, 113, 5322-5363; c) J. J. Douglas, J. D. Nguyen, K. P. Cole,
C. R. J. Stephenson, Aldrichim. Acta 2014, 47, 15-25; e) D. M. Schultz,
T. P. Yoon, Science 2014, 343, 985-994.
[14]
a) A. Studer, T. Vogler, Synthesis 2008, 1979-1993; b) B. L. Ryland, S.
S. Stahl, Angew. Chem. 2014, 126, 8968-8983; Angew. Chem. Int. Ed.
2014, 53, 8824-8838.
[15] N. A. Romero, K. A. Margrey, N. E. Tay, D. A. Nicewicz, Science 2015,
349, 1326-1330.
[16] a) X. Lang, J. Zhao, X. Chen, Angew. Chem. 2016, 128, 4775-4778;
Angew. Chem. Int. Ed. 2016, 55, 4697-4700.
[17]
a) J. Xuan, T.-T. Zeng, Z.-J. Feng, Q.-H. Deng, J.-R. Chen, L.-Q. Lu,
W.-J. Xiao, H. Alper, Angew. Chem. 2015, 127, 1645-1648; Angew.
Chem. Int. Ed. 2015, 54, 1625-1628; b) J. Xuan, T.-T. Zeng, J.-R. Chen,
L.-Q. Lu, W.-J. Xiao, Chem. Eur. J. 2015, 21, 4962-4965.
[4]
[5]
For recent reviews on photocatalysis-mediated cooperative catalysis,
see: a) M. N. Hopkinson, B. Sahoo, J.-L. Li, F. Glorius, Chem. Eur. J.
2014, 20, 3874-3886; b) C. Wang, Z. Lu, Org. Chem. Front. 2015, 2,
179-190; c) E. Meggers, Chem. Commun. 2015, 51, 3290-3301; d) J. J.
Murphy, P. Melchiorre, Nature 2015, 524, 297-298.
[18] a) Z. Shi, C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3381-
3430; b) S. D. McCann, S. S. Stahl, Acc. Chem. Res. 2015, 48, 1756-
1766.
For selected examples, see: a) D. A. Nicewicz, D. W. C. MacMillan,
Science 2008, 322, 77-80; b) H.-W. Shih, M. N. Vander Wal, R. L.
Grange, D. W. C. MacMillan, J. Am. Chem. Soc. 2010, 132, 13600-
13603; c) M. Neumann, S. Füldner, B. König, K. Zeitler, Angew. Chem.
2011, 123, 981-985; Angew. Chem. Int. Ed. 2011, 50, 951-954; d) F. R.
Petronijević, M. Nappi, D. W. C. MacMillan, J. Am. Chem. Soc. 2013,
135, 18323-18326; e) Y. Zhu, L. Zhang, S. Luo, J. Am. Chem. Soc.
2014, 136, 14642-14645; f) J. D. Cuthbertson, D. W. MacMillan, Nature
2015, 519, 74-77.
[19] a) H. Kotani, K. Ohkubo, S. Fukuzumi, J. Am. Chem. Soc. 2004, 126,
15999-16006; b) S. Fukuzumi, H. Kotani, K. Ohkubo, S. Ogo, N. V.
Tkachenko, H. Lemmetyinen, J. Am. Chem. Soc. 2004, 126, 1600-1601.
[20] See the Supporting Information for more details.
[21] CCDC 1472087 (2n) and 1472086 (3a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[6]
[7]
a) D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2012, 134, 8094-8097;
b) G. Bergonzini, C. S. Schindler, C. J. Wallentin, E. N. Jacobsen, C. R.
Stephenson, Chem. Sci. 2014, 5. 112-116.
[22] a) M. H. V. Huynh, T. J. Meyer, Chem. Rev. 2007, 107, 5004-5064; b) J.
Hartung, Eur. J. Org. Chem. 2001, 2001, 619-632.
[23] a) M. K. Zhu, J. F. Zhao, T. P. Loh, J. Am. Chem. Soc. 2010, 132, 6284-
6285; b) X.-L. Yang, F. Chen, N.-N. Zhou, W. Yu, B. Han, Org. Lett.
2014, 16, 6476-6479.
a) D. S. Hamilton, D. A. Nicewicz, J. Am. Chem. Soc. 2012, 134, 18577-
18580; b) T. M. Nguyen, D. A. Nicewicz, J. Am. Chem. Soc. 2013, 135,
9588-9591; c) A. J. Perkowski, D. A. Nicewicz, J. Am. Chem. Soc. 2013,
135, 10334-10337; d) D. J. Wilger, J. M. Grandjean, T. R. Lammert, D.
A. Nicewicz, Nat. Chem. 2014, 6, 720-726.
[24] a) T. Koike, Y. Yasu, M. Akita, Chem. Lett. 2012, 41, 999-1001; b) J. P.
Blinco, J. L. Hodgson, B. J. Morrow, J. R. Walker, G. D. Will, M. L.
Coote, S. E. Bottle, J. Org. Chem. 2008, 73, 6763-6771; c) J. L.
Hodgson, M. Namazian, S. E. Bottle, M. L. Coote, J. Phys. Chem. A
2007, 111, 13595-13605.
[8]
[9]
a) M.-Y. Cao, X. Ren, Z. Lu, Tetrahedron Lett. 2015, 56, 3732-3742; b)
M. Akita, T. Koike, Synlett 2013, 24, 2492-2505.
For selected reviews on the chemistry of N-centered radicals, see: a) S.
Z. Zard, Chem. Soc. Rev. 2008, 37, 1603-1618; b) J.-R. Chen, X.-Q.
Hu, L.-Q. Lu, W.-J. Xiao, Chem. Soc. Rev. 2016, 45, 2044-2056.
[25] a) Q. Lu, J. Zhang, G. Zhao, Y. Qi, H. Wang, A. Lei, J. Am. Chem. Soc.
2013, 135, 11481-11484; b) H. Wang, Q. Lu, C. Qian, C. Liu, W. Liu, K.
Chen, A. Lei, Angew. Chem. 2016, 128, 1106-1108; Angew. Chem. Int.
Ed. 2016, 55, 1094-1097; c) B. C. Giglio, V. A. Schmidt, E. J. Alexanian,
J. Am. Chem. Soc. 2011, 133, 13320-13322.
[10] a) G. Cecere, C. M. Konig, J. L. Alleva, D. W. MacMillan, J. Am. Chem.
Soc. 2013, 135, 11521-11524; b) L. J. Allen, P. J. Cabrera, M. Lee, M.
S. Sanford, J. Am. Chem. Soc. 2014, 136, 5607-5610; c) J. Davies, S.
G. Booth, S. Essafi, R. A. W. Dryfe, D. Leonori, Angew. Chem. 2015,
127, 14223-14227; Angew. Chem. Int. Ed. 2015, 54, 14017-14021; d) T.
W. Greulich, C. G. Daniliuc, A. Studer, Org. Lett. 2015, 17, 254-257; e)
H. Jiang, X. An, K. Tong, T. Zheng, Y. Zhang, S. Yu, Angew. Chem.
[26]
L. Tamborini, A. Pinto, T. K. Smith, L. L. Major, M. C. Iannuzzi, S.
Cosconati, L. Marinelli, E. Novellino, L. Lo Presti, P. E. Wong, M. P.
Barrett, C. De Micheli, P. Conti, ChemMedChem 2012, 7, 1623-1634.

Chemistry - A European Journal
10.1002/chem.201602597
COMMUNICATION
Organophotocatalysis
Xiao-Qiang Hu, Jun Chen, Jia-Rong
Chen,* Dong-Mei Yan, and Wen-Jing
Xiao
Page No. – Page No.
Organophotocatalytic Generation of
N- and O-Centred Radicals Enable
Aerobic Oxyamination and
Dioxygenation of Alkenes
cooperative catalysis: A cooperative TEMPO and photoredox catalytic
strategy was applied for the first time to the direct conversion of N-H and O-H
bonds into N- and O-centred radicals, enabling a general and selective
oxidative radical oxyamination and dioxygenation of various β,γ-unsaturated
hydrazones and oximes. In the reaction, O2 was employed not only as a
terminal oxidant but also as the oxygen source. This protocol provides
efficient access to the synthesis of various synthetically and biologically
important pyrazoline, pyridazine and isoxazoline derivatives under metal-free
and mild reaction conditions. Mechanistic studies revealed that the
cooperative organophotocatalytic system functions via two single-electron
transfer (SET) processes.