Metal bridging for directing and accelerating electron transfer as exemplified by harnessing the reactivity of AIBN

Article abstract of DOI:10.1002/anie.201411974

A new strategy for tuning the electron transfer between radicals and enolates has been developed. This method elicits the innate reactivity of AIBN with a copper catalyst and enables a cascade reaction with cinnamic acids. Electron paramagnetic resonance studies and control experiments indicate that the redox-active copper species not only activates the radical by coordination, but also serves as a bridge to bring the radical and nucleophile within close proximity to facilitate electron transfer. By exploiting possible combinations of redox-active metals and radical entities with suitable coordinating functional groups, this strategy should contribute to the development of a broad range of radical-based reactions.

Full text of DOI:10.1002/anie.201411974

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201411974
German Edition: DOI: 10.1002/ange.201411974
Radical Cascades
Metal Bridging for Directing and Accelerating Electron Transfer as
Exemplified by Harnessing the Reactivity of AIBN**
Yinjun Xie, Shengmei Guo, Longmin Wu, Chungu Xia, and Hanmin Huang*
Abstract: A new strategy for tuning the electron transfer
between radicals and enolates has been developed. This
method elicits the innate reactivity of AIBN with a copper
catalyst and enables a cascade reaction with cinnamic acids.
Electron paramagnetic resonance studies and control experi-
ments indicate that the redox-active copper species not only
activates the radical by coordination, but also serves as a bridge
to bring the radical and nucleophile within close proximity to
facilitate electron transfer. By exploiting possible combinations
of redox-active metals and radical entities with suitable
coordinating functional groups, this strategy should contribute
to the development of a broad range of radical-based reactions.
E
lectron transfer between molecules is a fundamental
process of many important transformations in biology and
chemistry that plays a vital role in controlling the reactivity
and selectivity of a reaction.[1] As a result, the design of
efficient catalysts and the discovery of effective activation
modes to direct and accelerate the electron transfer between
molecules are two important issues in catalysis. In this
context, a successful and intensively studied approach to
promote electron transfer is based on the use of transition
metals to bridge reactants through coordination.[2] Upon
coordination, the LUMO of an electrophile is reduced in
energy, and the resulting assembly provides a suitable envi-
ronment for facilitating electron transfer (Scheme 1a).
Whereas such a strategy is commonly employed for polar
reactions, its use for harnessing the reactivity of free radicals
remains, to the best of our knowledge, largely unexplored,
despite the significant advances in radical chemistry over the
last few decades.[3]
Scheme 1. New strategy for the activation of free radicals.
radicals or the transformation of radicals into their ionic
counterparts, rather than activating them for directing the
bond formation.[5] However, once a suitable coordinating
functional group has been introduced in a free radical, it
should be possible to activate the radical for directing bond
formation by coordination to a metal. AIBN [azobis(isobu-
tyronitrile)] is one of the most widely used radical initiators in
polymer chemistry and radical-mediated organic synthesis. It
usually does not get involved as a reactant in either radical or
polar reactions, although AIBN might be used as a cyanide
source in organic synthesis. This is in part due to the
inherently low nucleophilicity and electrophilicity of the
isobutyronitrile radical derived from AIBN.[6] Inspired by the
fact that the nitrile group is a known ligand for various metals,
we envisioned that the isobutyronitrile radical would be
activated by coordination to a metal, and that the electron
transfer between the radical and a nucleophile would
consequently be accelerated (Scheme 1b).[7a]
The successful implementation of this strategy calls for the
identification of a redox-active metal catalyst that not only
coordinates to the isobutyronitrile radical, but is also prone to
accepting one electron from a nucleophile. It is also essential
to carefully select a suitable nucleophile that could bind to the
metal center to ensure that a single electron transfer (SET)
process occurs. Copper salts, which have not only been shown
to be robust redox-active catalysts for both two-electron and
single-electron processes, but also good Lewis acids for nitrile
coordination, were selected as possible catalysts.[8] Zwitter-
ionic enolates generated in a Morita–Baylis–Hillman (MBH)
reaction[9] were chosen as the nucleophiles for testing our
hypothesis for the following reasons: 1) Enolates can act as
electron donors to participate in metal-mediated SET reac-
tions,[10] and 2) functional groups contained in the zwitterionic
enolates could provide useful binding sites to coordinate
Free radicals have long been recognized as highly reactive
species in many transformations; however, challenges related
to selectively controlling their reactivity are often encoun-
tered.[4] More and more radical reactions that involve
transition metals have been developed. Generally, the role
of the transition metal is limited to the generation of free
[*] Dr. Y. Xie, Dr. S. Guo, Prof. L. Wu, Prof. C. Xia, Prof. Dr. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou 730000 (China)
E-mail: hmhuang@licp.cas.cn
[**] This research was supported by the Chinese Academy of Sciences,
the National Natural Science Foundation of China (21222203,
21372231, and 21133011). We thank Prof. Yu Lan of Chongqing
University for theoretical calculations and helpful discussions.
AIBN=azobis(isobutyronitrile).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411974.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
a metal. We thus selected cinnamic acids (1) as suitable
substrates because of their electron-deficient nature and the
possibility of the carboxylate moiety acting as a ligand for
copper (Scheme 1c). It was expected that exposure of 1 to
a suitable tertiary amine in the presence of a copper salt
would furnish a zwitterionic enolate A, which might capture
the isobutyronitrile radical to form complex B. The coordi-
nation of the radical, which results in a lower-energy SOMO,
together with the well-organized aggregation would facilitate
the SET between radical and enolate. Herein, we report a new
strategy to direct and accelerate the electron transfer between
free radicals and enolates, which enabled the development of
a new cascade reaction between AIBN and a,b-unsaturated
acids. This method provides a rapid approach for the synthesis
of functionalized pyrrolidine-2,5-diones, which are important
moieties in a wide range of biologically active molecules.[11]
To put our design into practice, the reaction of cinnamic
acid (1a) and AIBN (2a) was first studied in the presence of
a catalytic amount of CuBr2 and a stoichiometric amount of
Et3N and Ag2CO3 (Table 1, entry 1). To our delight, hetero-
as the catalyst, other reaction parameters were screened to
maximize the efficiency of this cascade reaction. The use of
1,4-diazabicyclo[2.2.2]octane (DABCO) as the amine and
Ag2CO3 as the oxidant gave the desired heterocycle in 59%
yield after heating at 1008C for twelve hours (see the
Supporting Information). As alcohols and H2O have been
shown to be beneficial for stabilizing the zwitterionic
intermediates in MBH reactions,[13] we screened several
alcohols as additives and found that 2-amino-3-phenylpro-
pan-1-ol (PPA) with H2O was optimal. Under these con-
ditions, compound 3aa was isolated in 74% yield with the
thermodynamically more stable Z isomer as the major
product (E/Z = 30:70; entry 14). Further control experiments
confirmed that the substrates were unreactive in the absence
of either copper salts or tertiary amines, indicating the
importance of the tertiary amine for generating the zwitter-
ionic enolate and of the copper catalysts for accelerating the
electron transfer (entries 15 and 16). Moreover, when some
typical MBH substrates, such as methyl cinnamate, chalcone,
and phenylbut-3-en-2-one,[9] were subjected to the optimized
reaction conditions, these a,b-unsaturated carbonyl com-
pounds were completely recovered (see the Supporting
Information). These observations strongly suggest that the
COOH moiety of 1a is a prerequisite for this reaction.
Table 1: Optimization of the reaction conditions.[a]
With the optimized conditions established, the generality
of this transformation was investigated. A series of cinnamic
acids with electron-donating or -withdrawing groups gave the
desired products 3aa–3ka in good yields (Table 2). The steric
Entry
[Cu]
Base
Additive
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
CuBr2
CuBr
CuCl2
CuI
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
–
–
–
–
–
–
–
–
–
120
120
120
120
120
120
120
100
80
100
100
100
100
100
100
100
37
44
42
11
24
21
59
59
51
60
59
63
70[f]
74[f]
0
Table 2: Substrate scope.[a]
Cu(OTf)2
[Cu(acac)2]
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
–
9
–
–
PPh3
EG
EG/H2O
PPA/H2O
–
–
10[b]
11[b]
12[b,c]
13[b,d]
14[b,e]
15[b]
16[b]
CuBr
0
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), [Cu] (0.05 mmol,
10 mol%), base (1.0 mmol), Ag2CO3 (1.0 mmol), and xylene (2 mL) at
1208C for 12 h. Yields were determined by GC analysis. E/Z ratios in the
range of 46:54 to 30:70. [b] 6 h. [c] EG (0.06 mmol). [d] EG (0.06 mmol),
H2O (0.3 mmol). [e] PPA (0.06 mmol), H2O (0.3 mmol). [f] Yield of
isolated product.
cycle 3aa, with a pyrrolidine-2,5-dione moiety, was obtained
in 37% yield when the reaction was conducted at 1208C in
xylene. The structure of 3aa was determined by single-crystal
X-ray diffraction analysis.[12] The product 3aa could be viewed
as the addition of two isobutyronitrile radicals to the cinnamic
acid skeleton. Afterwards, we started to optimize the reaction
conditions by screening different copper catalysts. As shown
in Table 1, both CuI and CuII salts can catalyze this trans-
formation, and CuBr was found to be the most efficient,
affording product 3aa in 44% yield (entries 1–6). With CuBr
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), CuBr (0.05 mmol,
10 mol%), Ag2CO3 (1.0 mmol), DABCO (1.0 mmol), PPA (0.06 mmol,
12 mol%), H2O (0.3 mmol), and xylene (2 mL) at 1008C for 6 h. Yields of
isolated products are given; the E/Z ratios were determined by GC
analysis before isolation. [b] EG (0.06 mmol, 12 mol%) was used instead
of PPA. [c] 10 h.
2
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
hindrance of the substituents on the aryl ring of the cinnamic
acids did not exert a strong influence on the reactivity (3ja vs.
3ka). Aside from the cinnamic acids, naphthyl-substituted
acrylic acid 1l was also effectively transformed into the
corresponding adduct 3la in 58% yield. Furthermore, the
method was proven to be equally effective for heteroaryl-
substituted acrylic acids (3ma, 3na, 3oa, and 3pa). Notably,
when the E-configured substrates 1m and 1n were used, only
the E isomers of the corresponding products were obtained
(3ma and 3na).[12] The high stereoselectivity for the E isomer
can be attributed to the heteroatoms in the ortho position of
the aromatic ring, which coordinate to the copper center
during the catalytic process. Finally, other nitrile-containing
radicals, derived from 2,2’-azobis(2-methylbutyronitrile)
O atom of the product originated from cinnamic acid, as no
18O-containing product was detected. Furthermore, when
a radical scavenger, such as 2,6-di-tert-butyl-4-methylphenol
(BHT) or 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO),
was added, the reaction was almost completely suppressed
(see the Supporting Information). These results demonstrated
that a radical process was involved in this reaction.
After confirming the origin of the N and O atoms in the
product, we further explored the roles of the copper and silver
salts. As cinnamic acid could react with CuBr and Ag2CO3 to
form the corresponding salts, the silver and copper cinnamate
salts were prepared separately and subjected to this reaction.
When cinnamic acid was replaced by cinnamoyloxysilver, the
reaction did not take place in the absence of a catalytic
amount of CuBr, revealing that the copper catalyst was
essential for this reaction (Scheme 2c,d). Meanwhile, when
bis(cinnamoyloxy)copper was used as the substrate instead of
cinnamic acid, product 3aa was obtained regardless of the
presence of a stoichiometric amount of Ag2CO3 (Scheme
2e,f). These observations indicate the essential role of copper
as a catalyst and that Ag2CO3 probably acts as an oxidant to
re-oxidize the CuI to a CuII species to close the catalytic cycle.
To get further insights into how the copper bridging
directs and accelerates the electron transfer in this reaction,
we investigated the interaction of the CuII species with the
reactants by electron paramagnetic resonance (EPR) spec-
troscopy.[14] As shown in Figure 1, initially, when a catalytic
amount of CuBr2 was treated with 1a (10 equiv) in DMSO at
1008C for two hours, the resulting solution exhibited a typical
axial CuII EPR signal (line 2), identical to that of a DMSO
solution of CuBr2 (line 1). Moreover, the strong EPR signal of
CuII with a lower g value was further observed when a catalytic
amount of CuBr2 was treated with 1a (10 equiv) and DABCO
(20 equiv) in DMSO at 1008C for two hours. These data
excluded the possibility that cinnamic acid 1a was trans-
formed into an electrophilic radical species by oxidation with
CuBr2 as no electron transfer occurred between the CuII
species and cinnamic acid. Furthermore, a typical axial CuII
EPR signal was also detected when CuBr2 was treated with
AIBN (20 equiv) in DMSO at 1008C for two hours. This
result indicated that SET did not take place between CuBr2
and the isobutyronitrile radical, ruling out the involvement of
an isobutyronitrile ion in the present reaction. Furthermore,
essentially the same CuII EPR signal was observed when
CuBr2 was exposed to AIBN (20 equiv) and cinnamic acid 1a
(10 equiv) in DMSO (1008C, 2 h), indicating that SET could
not occur in the absence of DABCO. We expected that once
DABCO had been introduced to the above system, the
zwitterionic enolate would form, and the SET process should
proceed rapidly. Indeed, when a catalytic amount of CuBr2
was treated with 1a (10 equiv), AIBN (20 equiv), and
DABCO (20 equiv) in DMSO at 1008C, the CuII EPR
signal quickly disappeared within ten minutes (Figure 1b),
and the desired cyclization product 3aa was detected by GC-
MS. Analysis of the copper residue by X-ray photoelectron
spectroscopy (XPS) indicated that a CuI species had been
formed (see the Supporting Information). These data
excluded the participation of isobutyronitrile ion and enolate
radical intermediates in this reaction and corroborated our
(AMBN)
and
1,1’-azobis(cyclohexane-1-carbonitrile)
(ACCN), also reacted with cinnamic acid (1a) to afford the
corresponding products 3ab and 3ac in 51% and 36% yield,
respectively. The product 3aa could be converted into
À
pyrrolidine-2,5-dione 6 by cleavage of the C N bond upon
exposure to KOH. Furthermore, 3aa could also be used as the
starting material for construction of the N-fused bicyclic
compound 7 in a one-step functional group transforma-
tion.
To get insights into the mechanism of this transformation,
several control experiments were conducted (Scheme 2).
Initially, when 15N-labeled AIBN (the azo nitrogen atoms
were labelled with 15N) was treated with 1a under the
standard conditions, the resulting product was analyzed by
high-resolution mass spectrometry, which showed that the 15
N
atoms of the azo moiety had not been incorporated into the
product. This result confirmed that the N atoms of the
product originated from the nitrile groups of AIBN. More-
over, the addition of two equivalents of H218O showed that the
amide was not formed by hydrolysis with H2O and that the
Scheme 2. Control experiments.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
DABCO cation and generate
intermediate D. For (E)-3-(thio-
phen-2-yl)acrylic acid and (E)-3-
(pyridin-2-yl)acrylic acid, which
feature heteroatoms at neighbor-
ing positions, the chelated inter-
mediate C’ might be involved,
leading to the exclusive formation
of the E isomer. Oxidation of the
CuI to the CuII species by AgI
increases its Lewis acidity and
enables the coordinated nitrile
to be attacked by an oxygen
À
anion to afford Cu N species E.
The active CuII species E captures
another isobutyronitrile radical
by coordination via its nitrile
group to form intermediate F.
Figure 1. a) EPR spectra of CuBr2 treated with different reactants; measured at 200 K. b) Evolution of
the EPR spectra of the standard reaction mixture with time; measured at 200 K.
À
Subsequent SET breaks the Cu
I
À
hypothesis that SET took place between the isobutyronitrile
radical and the zwitterionic enolate derived from cinnamic
acid. Therefore, activation mode B (Scheme 1c) most likely
constitutes the approach of the isobutyronitrile radical to the
zwitterionic enolate in this cascade reaction.
On the basis of the control experiments and EPR studies,
a reaction mechanism was proposed (Figure 2). Initially,
exposure of 1a to the copper salt in the presence of DABCO
and the silver salt leads to the generation of zwitterionic
enolate A, which captures the free isobutyronitrile radical
(generated from AIBN) to form intermediate B. The coordi-
nation of the nitrile group to the CuII species renders the
radical species more electrophilic, and the resulting Cu bridge
brings the radical and the enolate closer together, facilitating
N bond and forms a C N bond, releasing a Cu species and
intermediate G. Finally, rearrangement[15] of G leads to
product 3aa.
Several additional experiments and analyses provided
further evidence for this mechanism. A cross-over experiment
with 1a, AIBN (2a), and AMBN (2b) as the reactants was
carried out under the standard conditions, and the products
3aa and 3ab were obtained together with the cross-over
products in a ratio of approximately 1:1:1. This result
confirmed that the delivery of the second radical to inter-
mediate F occurred in an intermolecular fashion (see the
Supporting Information).[16] Trace amounts of 2,2-dimethyl-4-
phenylbut-3-enenitrile and 4-benzylidene-3,3-dimethylpyrro-
lidine-2,5-dione were detected in the standard reaction,
suggesting the plausible intermediacy of D in the catalytic
cycle. Moreover, when 4-benzylidene-3,3-dimethylpyrroli-
dine-2,5-dione was treated with AIBN under the standard
conditions, the desired product 3aa was not detected,
indicating the necessity of the intermediacy of E or F in the
catalytic cycle. Computational studies revealed that the
SOMO energy of the isobutyronitrile radical was indeed
reduced by 1.59 eV when the radical was coordinated to
a copper species (see the Supporting Information), which is
consistent with our initial hypothesis.
the SET between radical and enolate through intermediate C
[7]
À
with the construction of a new C C bond. Subsequently,
a retro-aza-Michael addition takes place to eliminate the
Finally, to explore this method in more complex settings,
substrates with two carbonyl groups were synthesized and
investigated under the reaction conditions. As such, (E)-4-
oxo-4-phenylbut-2-enoic acid (4a) was identified as a desir-
able substrate for testing the practicability of our strategy.
Using the procedure in Table 3, the cascade reaction with
AIBN afforded cyclization product 5aa in 66% yield. As
expected, the keto carbonyl group remained intact, and the
reaction took place exclusively at the carboxyl group, afford-
ing the E isomer as the sole product.[12] Similar results were
obtained with aryl- and alkyl-substituted unsaturated keto-
acids. The desired reactions proceeded smoothly to give the
corresponding products in moderate to good yields with
completely E selectivity under the current reaction condi-
tions.
Figure 2. Plausible reaction mechanism.
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 3: Unsaturated ketoacids as substrates.[a]
[3] a) Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi),
Wiley-VCH, Boca Raton, 2001; b) A. Studer, D. P. Curran,
Angew. Chem. Int. Ed. 2011, 50, 5018; Angew. Chem. 2011, 123,
5122; c) A. Studer, D. P. Curran, Nat. Chem. 2014, 6, 765.
[4] B. Quiclet-Sire, S. Z. Zard, Pure Appl. Chem. 1997, 69, 645.
[5] For reviews, see: a) J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev.
1994, 94, 519; b) L. Ford, U. Jahn, Angew. Chem. Int. Ed. 2009,
48, 6386; Angew. Chem. 2009, 121, 6504; c) U. Jahn, Top. Curr.
Chem. 2012, 320, 121; d) U. Jahn, Top. Curr. Chem. 2012, 320,
191; e) U. Jahn, Top. Curr. Chem. 2012, 320, 323; f) Q. Liu, R.
Jackstell, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 13871;
Angew. Chem. 2013, 125, 14115; g) L. J. Sebren, J. J. Devery III,
C. R. J. Stephenson, ACS Catal. 2014, 4, 703; h) S. Sumino, A.
Fusano, T. Fukuyama, I. Ryu, Acc. Chem. Res. 2014, 47, 1563.
[6] F. De Vleeschouwer, V. Van Speybroeck, M. Warroquier, P.
Geerlings, F. De Proft, Org. Lett. 2007, 9, 2721.
[7] a) M. H. Dickman, R. J. Doedens, Inorg. Chem. 1983, 22, 1591;
b) M. Nakashima, M. Mikuriya, Y. Muto, Bull. Chem. Soc. Jpn.
1985, 58, 968; c) Y. Muto, A. Sasaki, T. Tokii, M. Nakashima,
Bull. Chem. Soc. Jpn. 1985, 58, 2572; d) J. Barluenga, L. A.
Lꢁpez, O. Lçber, M. Tomꢂs, S. Garcꢃa-Granda, C. Alvarez-Rffla,
J. Borge, Angew. Chem. Int. Ed. 2001, 40, 3392; Angew. Chem.
2001, 113, 3495; e) J. Irangu, M. J. Ferguson, R. B. Jordan, Inorg.
Chem. 2005, 44, 1619.
[a] Reaction conditions: 4 (0.5 mmol), 2 (1.0 mmol), Cu(BF4)2·H2O
(0.05 mmol, 10 mol%), Ag2CO3 (1.0 mmol), DABCO (1.0 mmol), EG
(0.06 mmol, 12 mol%), H2O (0.3 mmol), and xylene (4 mL) at 1008C for
3 h. Yields of isolated products are given. [b] 1208C. [c] 908C.
In summary, we have developed a conceptually new
strategy for directing and accelerating the single electron
transfer between free radicals and enolates by bridging the
two reactants with a metal species. A redox-active copper
species was used for the activation of the free radical and for
bringing the radical and enolate closer together to facilitate
electron transfer. We demonstrated the remarkable ability of
this strategy for harnessing the reactivity of the isobutyroni-
trile radical, which is generally not considered as a structural
contributor. This approach enabled the development of
a cascade reaction for the synthesis of highly functionalized
pyrrolidine-2,5-diones from readily available cinnamic acids
and AIBN. We believe that these results may inspire future
research efforts towards the development of transition-metal-
catalyzed radical reactions, especially those featuring radical
species as electrophilic intermediates.
[8] a) J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325;
b) M. Meldal, C. W. Tornoe, Chem. Rev. 2008, 108, 2952; c) C.
Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464; d) A.
Casitas, X. Ribas, Chem. Sci. 2013, 4, 2301; e) S. R. Chemler,
Science 2013, 341, 624.
[9] Y. Wei, M. Shi, Chem. Rev. 2013, 113, 6659.
[10] a) M. Schmittel, A. Haeuseler, J. Organomet. Chem. 2002, 661,
169; b) T. Amatov, U. Jahn, Angew. Chem. Int. Ed. 2011, 50,
4542; Angew. Chem. 2011, 123, 4636.
[11] a) A. J. Kirby, R. Lelain, P. Mason, F. Maharlouie, P. J. Nicholls,
H. J. Smith, C. Simons, J. Enzyme Inhib. Med. Chem. 2002, 17,
321; b) S.-C. Chien, M.-L. Chen, J. Agric. Food Chem. 2008, 56,
7017; c) K. Kaminski, J. Obniska, Bioorg. Med. Chem. 2008, 16,
4921.
[12] CCDC 932845 (3aa), 946349 (3na), and 932846 (5aa) 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.
Keywords: AIBN · cinnamic acids · copper · enolates ·
single-electron transfer
[13] a) V. K. Aggarwal, A. Mereu, G. J. Tarver, R. McCague, J. Org.
Chem. 1998, 63, 7183; b) R. Lee, F. Zhong, B. Zheng, Y. Meng, Y.
Lu, K. Huang, Org. Biomol. Chem. 2013, 11, 4818.
[14] G. Micera, S. Deiana, L. Erre, P. Piu, A. Panzanelli, J. Chem.
Educ. 1984, 61, 646.
[15] D. M. Arnott, P. J. Harrison, G. B. Henderson, Z.-C. Sheng, F. J.
Leeper, A. R. Battersby, J. Chem. Soc. Perkin Trans. 1989, 265.
[16] The kinetic isotope effects observed in intermolecular competi-
tion experiments (kH/kD = 1.52) suggested that the cleavage of
[1] For selected reviews on electron transfer, see: a) L. Eberson,
Adv. Phys. Org. Chem. 1982, 18, 79; b) A. Pross, Acc. Chem. Res.
1985, 18, 212; c) J. K. Kochi, Acc. Chem. Res. 1992, 25, 39; d) A.
Houmam, Chem. Rev. 2008, 108, 2180; e) B. M. Rosen, V. Percec,
Chem. Rev. 2009, 109, 5069; f) A. Kumar, M. D. Sevilla, Chem.
Rev. 2010, 110, 7002; g) J. L. Dempsey, J. R. Winkler, H. B. Gray,
Chem. Rev. 2010, 110, 7024; h) C. M. Paquete, R. O. Louro, Acc.
Chem. Res. 2014, 47, 56; i) R. Pꢀrez-Ruiz, M. C. Jimꢀnez, M. A.
Miranda, Acc. Chem. Res. 2014, 47, 1359; j) J. Broggi, T. Terme,
P. Vanelle, Angew. Chem. Int. Ed. 2014, 53, 384; Angew. Chem.
2014, 126, 392.
À
the olefinic C H bond at the a-position of cinnamic acid is not
involved in the rate-limiting step. See the Supporting Informa-
tion for details.
[2] a) Lewis acids and selectivity in organic synthesis (Eds.: J. M.
Pons, M. Santelli), CRC, Boca Raton, 1996; b) Lewis acids in
organic synthesis (Ed.: Y. Yamamoto), Wiley-VCH, Weinheim,
2000; c) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209;
d) Y. Yamamoto, J. Org. Chem. 2007, 72, 7817.
Received: December 12, 2014
Revised: February 11, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Radical Cascades
Electron bridge: An efficient strategy for
improving the electron transfer between
radicals and enolates has been devel-
oped. A redox-active copper species acti-
vates the free radical and brings the
radical and enolate within proximity,
which in turn facilitates the electron
transfer. Thus, a cascade reaction for the
synthesis of highly functionalized pyrroli-
dine-2,5-diones was developed.
Y. Xie, S. Guo, L. Wu, C. Xia,
H. Huang*
&&&& — &&&&
Metal Bridging for Directing and
Accelerating Electron Transfer as
Exemplified by Harnessing the Reactivity
of AIBN
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!