Visible-light-induced photoreductive generation of radicals from epoxides and aziridines

Article abstract of DOI:10.1002/anie.201007571

It's a trap! Both epoxides and aziridines substituted by an aryl ketone can be reduced efficiently using visible-light photoredox catalysts. The radicals generated were trapped by allyl sulfones, and formed α-branched β-hydroxy or amino derivatives with high diastereocontrol (see scheme; dtbbpy=4,4′-di-tert-butyl-2,2′-bipyridine, ppy=2-phenylpyridine). Copyright

Full text of DOI:10.1002/anie.201007571

DOI: 10.1002/anie.201007571
Photoredox Catalysis
Visible-Light-Induced Photoreductive Generation of Radicals from
Epoxides and Aziridines**
Marie-Hꢀlꢁne Larraufie, Rꢀmy Pellet, Louis Fensterbank,* Jean-Philippe Goddard,
Emmanuel Lacꢂte, Max Malacria, and Cyril Ollivier*
As a result of its unique features, radical chemistry has
become a reliable and efficient tool for synthetic chemists
over the last fifty years.[1] Nowadays, the necessity to devise
ecocompatible alternatives for the generation of radical
species has stimulated intense research efforts.[2] The devel-
opment of single-electron transfer (SET) redox processes
using catalytic amounts of metal complexes would be a
significant advance. For that purpose, the use of visible light
[3]
and a photoredox catalyst such as [Ru(bpy)3]Cl2 has lately
appeared to offer very promising possibilities.[4] Thus, follow-
Scheme 1. Photocatalytic reductive ring opening of epoxides and
subsequent carbon–carbon bond formation.
ing the pioneering findings of Cano-Yelo and Deronzier,[5]
recent contributions from the research groups of Yoon,
MacMillan, and Stephenson have demonstrated that
enones,[6] perfluorated iodides,[7] as well as activated chlorides
and bromides[8] are suitable substrates for the formation of
radicals by visible light-catalyzed reductive electron transfers.
Because epoxides are exquisite substrates for radical
transformations,[9] we envisioned to expand the scope of
visible light photoredox catalysis to the ring opening of these
moieties, and access a formal photocatalytic Nugent–Rajan-
Babu–Gansꢀuer[10] reaction. Owing to their low redox poten-
tial (À2.35 V for stilbene oxide vs. Ag/AgI)[11] compared to
[Ru(bpy)3]2+/[Ru(bpy)3]+ (À1.33 V vs. SCE), we quickly
abandoned our initial approach based on direct electron
transfer to the oxirane, but we installed an a-carbonyl moiety
as a relay. Ring opening of a-ketoepoxides[12] has been
sporadically reported under UV irradiation[13] and our goal
was first to develop an alternative using low-energy visible-
light activation. Then, the photogenerated radical could be
exploited in the context of carbon–carbon bond formation
(Scheme 1).[14] Our results are presented herein.
Our preliminary investigation was carried out on epoxy-
chalcone 1a (Table 1). First, we tested the Stephenson
conditions used for dehalogenation[8b] (i.e. [Ru(bpy)3]Cl2-
·(H2O)6 (5 mol%), iPr2NEt (2 equiv), and Hantzsch ester
(1.1 equiv) in DMF). After 36 hours of irradiation with a
Table 1: Optimization of the photoreduction conditions for epoxychal-
cone 1a.[a]
Entry
Solvent
n
t [h]
Conv. [%][b]
Yield [%][c]
1
2
3
4
5
DMF
MeCN
Et2O
DMSO
DMSO
2
2
2
2
0
36
36
36
3
76
30
0
100
100
74
10
0
86
91
[*] M.-H. Larraufie, R. Pellet, Prof. Dr. L. Fensterbank, Dr. J.-P. Goddard,
Dr. E. Lacꢀte,[+] Prof. Dr. M. Malacria, Dr. C. Ollivier
UPMC Univ Paris 06
3
Institut Parisien de Chimie Molꢁculaire (UMR CNRS 7201)-FR 2769
4 place Jussieu, C. 229, 75005 Paris (France)
Fax: (+33)1-4427-7360
E-mail: louis.fensterbank@upmc.fr
cyril.ollivier@upmc.fr
Homepage: http://www.ipcm.fr/
[a] Reaction conditions: 1a (0.1 mmol, 0.1m in solvent), 3 (0.11 mmol),
[Ru(bpy)3]Cl2·(H2O)6 (0.005 mmol), irradiation with a 14 W fluorescent
1
light bulb at room temperature. [b] Conversion determined by H NMR
analysis. [c] Yield of isolated product. bpy=2,2’-bipyridine, DMF=N,N-
dimethylformamide, DMSO=dimethyl sulfoxide.
[+] Present address:
Institut de Chimie des Substances Naturelles CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
14 W fluorescent lamp, b-hydroxyketone 2a was obtained in
74% yield with incomplete conversion of 1a.
[**] We thank UPMC, CNRS, IUF (L.F., M.M.), and ANR (grant
“Credox”). M.-H.L. was awarded a graduate fellowship by the
Rꢁgion Ile-de-France, which is gratefully acknowledged. We warmly
thank Dr. Carlos Afonso (IPCM) for technical assistance (LC-MS
measurements). Analytical equipment was generously offered
through FR 2769.
A rapid solvent screening indicated that DMSO was the
best solvent. Finally, it became apparent that the Hantzsch
ester could be both the reductive quencher and the hydrogen
and proton donor. Indeed, in a typical reduction, 1a led to
91% of 2a after 3 hours of irradiation at room temperature in
DMSO, in the presence of the Hantzsch ester (1.1 equiv) and
[Ru(bpy)3]Cl2·(H2O)6 (5 mol%) only.[15]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007571.
Angew. Chem. Int. Ed. 2011, 50, 4463 –4466
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4463

Communications
Table 2: Scope of the epoxide ring-opening reaction and extension to
aziridines.[a]
Table 3: Influence of the nature of the photocatalyst and the additives on
the substrate scope.
Entry
X
R1
R2
t [h]
Yield [%][b]
Entry
Substrate
t [h] Conditions[a] Yield [%][b]
1
2
3
4
5
6
7
8
O
O
O
O
O
O
O
O
C6H5
C6H5
C6H5
C6H5
C6H5
3
7
5
20
10
4
3
24
3
3
3
2a, 91
2b, 76
2c, 76
2d, 55
2e, 42
2 f, 78
2g, 86
2h, 52
2i, 94
2j, 81
2k, 78
1
2
3
15
72
15
A
B
C
2l, 0
2l, 55
2l, 75
4-MeOC6H4
4-CF3C6H4
4-CO2MeC6H4
napht
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
C6H5
1l
C6H5
4
5
15
15
A
C
2m, 0
2m, 83
(d.r.=54:46)
4-CF3C6H4
4-ClC6H4
C4H9
C6H5
C6H5
1m
1n
9
10
11
NTs
NTs
NTs
6
7
15
4
A
C
2n, 0
2n, 87
(d.r.=76:24)
C4H9
[a] Reaction conditions: substrate (0.2 mmol, 0.1m in DMSO), 3
(0.22 mmol), [Ru(bpy)3]Cl2·(H2O)6 (0.01 mmol), irradiation with a 14 W
fluorescent light bulb at room temperature. [b] Yield of isolated product.
napht=naphthyl, Ts=4-toluenesulfonyl.
[a] Conditions A: substrate (0.2 mmol, 0.1m in DMSO), 3 (0.22 mmol),
[Ru(bpy)3]Cl2·(H2O)6 (0.01 mmol); Conditions B: substrate (0.2 mmol,
0.1 mm in DMSO), 3 (0.22 mmol), iPr2NEt (0.22 mmol), [Ru(bpy)3]
Cl2·(H2O)6 (0.01 mmol); Conditions C: substrate (0.2 mmol, 0.1 mm in
DMSO), 3 (0.22 mmol), iPr2NEt (0.22 mmol), [Ir(dtbbpy)(ppy)2]PF6
(0.01 mmol) [b] Yield of isolated product. dtbbpy=4,4’-di-tert-butyl-
2,2’-bipyridine, ppy=2-phenylpyridine.
With the optimized conditions in hand, we examined the
scope of the process (Table 2). The ring opening worked
smoothly with epoxychalcones bearing electron-donating
(Table 2, entry 2), or -withdrawing substituents (Table 2,
entries 3, 4, and 6) on both aromatic rings. The mild
conditions were compatible with a range of functionalities
including an ether (Table 2, entry 2), an ester (Table 2,
entry 4), an aromatic halide (Table 2, entry 7), or a naphthyl
ring (Table 2, entry 5). When the carbonyl substituent R2 was
an alkyl chain, no conversion could be observed. However,
when the oxirane substituent R1 was a butyl chain, the desired
reduction proceeded as desired. Interestingly, tosylaziridines
were reduced under the same conditions in quite high yields
(Table 2, entries 9–11). To our knowledge, these represent the
first examples of photocatalyzed ring opening of aziridines
which are substrates that have not been yet reported to be
reactive in titanocene chemistry.
Limitations were encountered with sterically hindered b-
epoxyketones. To bypass this problem, we first reintroduced
iPr2NEt as a better reductive quench than Hantzsch ester 3
(Table 3, conditions B). We were pleased to observe that the
desired reduction of substrate 1l bearing a bulky mesityl
substituent occurred, even if the conversion remained incom-
plete after 72 hours of irradiation (75% conversion, 55%
yield; Table 3, entry 2). Anticipating that a stronger reductant
would favor the photoreductive process, we switched the
catalyst from [Ru(bpy)3]Cl2·(H2O)6 to [Ir(dtbbpy)(ppy)2]PF6
complex[16] (À1.51 V vs. SCE for [Ir(dtbbpy)(ppy)2]+/[Ir-
(dtbbpy)(ppy)2]; conditions C).[17] Pleasingly, we obtained a
full conversion for 1l after 15 hours of irradiation (100%
conversion, 75% yield, entry 3). Then, applying those con-
ditions to substrates 1m and 1n bearing a substituent in the
a position to the ketone, we were delighted to observe that
the photoreduction took place with a total conversion and
synthetically useful yields (Table 3, entries 5 and 7).
Table 4: Optimization of the allylation conditions on epoxychalcone1a.[a]
Entry
n
Catalyst
HE t [h] Yield of
Yield of
2a [%][b] 8a [%][b]
1
2
3
4
5
10 [Ru(bpy)3]Cl2·(H2O)6
10 [Ru(bpy)3]Cl2·(H2O)6
10 [Ru(bpy)3]Cl2·(H2O)6
10 [Ir(dtbbpy)(ppy)2]PF6
3
4
5
5
5
5
12
24
48
48
30
23
0
<5
<5
41
51
0
65
67
3
[Ir(dtbbpy)(ppy)2]PF6
[a] Reaction conditions: substrate (0.2 mmol, 0.1m in DMSO), 3–5
(0.42 mmol), catalyst (0.01 mmol), irradiation with a 14 W fluorescent
light bulb at room temperature. [b] Yield of isolated product. HE=
Hantzsch ester, Tol=tolyl.
alents of allylsufone 6 prior to irradiation under conditions A
led to a-allyl ketone 8a in 41% yield, albeit together with
30% of directly reduced 2a (Table 4, entry 1). We decided to
take advantage of the kinetic isotope effect to favor allylation
over reduction[18] and switched to 4,4’-[D2]-Hantzsch ester 4.
This led to an improved ratio of allyl product (2:1; Table 4,
entry 2). Reasoning that the substitution at the 4-position of
Hantzsch esters might be determining for the balance
between direct reduction and allylation, we also tested 4-
Me-Hantzsch ester 5. No conversion was observed when
[Ru(bpy)3]Cl2·(H2O)6 was used (Table 4, entry 3). However,
We next attempted to engage the photogenerated radical
in an allylation process (Table 4). Introduction of 10 equiv-
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Angew. Chem. Int. Ed. 2011, 50, 4463 –4466

the use of [Ir(dtbbpy)(ppy)2]PF6 allowed us to selectively
obtain the allylation product 8a (Table 4, entry 4). Pleasingly,
lowering the amount of allylating agent to only 3 equivalents
of allyl sulfone did not affect this good selectivity (Table 4,
entry 5).
The scope of this new radical allylation sequence was
examined next (Table 5). A variety of b-epoxyketones
(Table 5, entries 1–4 and 7) and tosylaziridines (Table 5,
Table 5: Scope of the photoallylation process.[a]
Scheme 2. Proposed mechanism for both photocatalyzed reduction
and reductive allylation of 1a.
Entry
X
Sulfone R1
R2
d.r.[b]
96:4
93:7
>95:5
>95:5
>95:5
>95:5
Yield [%][c]
To conclude, we have extended the scope of visible-light
photoredox catalysis to the generation of radicals from
epoxides and aziridines. To perform this process, we used
either [Ir(dtbbpy)(ppy)2]+ or [Ru(bpy)3]2+ as the photocata-
lyst in combination with a Hantzsch ester derivative as both
quencher and hydrogen donor. Then, we took advantage of
the reactivity of the photogenerated radical to create new
carbon–carbon bonds through a highly diastereoselective
radical ring-opening/allylation tandem process. Extension to
other radical acceptors and related mechanistic studies are
still underway. Further work will examine cyclizations and the
viability of asymmetric approaches by simply starting from
corresponding enantioenriched epoxides or for the desym-
metrization of meso-epoxides.
1
2
3
4
5
6
7
8
O
O
O
O
NTs
NTs
O
6
6
6
6
6
6
7
7
C6H5 C6H5
8a, 67
8b, 73
8e, 51
8h, 70
8i, 49
8j, 46
C6H5 4-MeOC6H4
C6H5 napht
C4H9 C6H5
C6H5 C6H5
C6H5 4-MeO6H4
C6H5 C6H5
90:10 9a, 60
87:13 9i, 43
NTs
C6H5 C6H5
[a] Conditions: substrate (0.2 mmol, 0.1m in DMSO), 5 (0.42 mmol),
allyl sulfone (0.6 mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.01 mmol), irradiation
with a 14 W fluorescent light bulb at room temperature. [b] Diastereo-
meric ratio (d.r.) was determined from the 1H NMR analysis of the crude
and isolated products and confirmed by LC-MS analysis. [c] Yield of
isolated product.
entries 5, 6, and 8) could be reduced and then allylated with Experimental Section
Synthesis of 8a: Hantzsch ester 5 (112 mg, 0.42 mmol, 2.1 equiv), allyl
fair to good yields, and excellent diastereoselectivities. Allyl
sulfone can be substituted by an electron-withdrawing
(Table 5, entries 1–6) as well as -donating (Table 5,
entries 7–8) group without loss in efficiency, although diaste-
reoselectivities for 9a and 9i are slightly altered. Notably,
such radical allylation would presumably not be possible in
the classical TiIII conditions because formation of the keto-
sulfone 6 (161 mg, 0.6 mmol, 3 equiv), epoxychalcone 1a (44 mg,
0.2 mmol, 1 equiv), and [Ir(dtbbpy)(ppy)2]PF6 (9.1 mg, 0.01 mmol,
5 mol%) were added to a dried Schlenk tube equipped with a stir bar.
The Schlenk tube was evacuated and backfilled with argon three
times, before degassed DMSO (2 mL) was added under argon. The
yellow reaction mixture was irradiated at RT with a 14 W fluorescent
light bulb for 48 h. The reaction was quenched with water (15 mL)
and extracted with EtOAc (3 ꢂ 10 mL). The combined organic layers
were dried over MgSO4, concentrated in vacuo, and purified by flash
chromatography on silica gel to afford 8a as a colorless oil (45 mg,
67%).
enolate as a result of the two-electrons reduction is fast.[12]
A
suitable crystal was obtained for aminoketone 8i, whose
structure was determined by X-ray analysis (see the Support-
ing Information).[19] The major diastereomer was shown to be
syn which is consistent with Guindonꢁs model for the radical
allylation of b-alkoxy esters under nonchelation control.[20]
A plausible mechanism is proposed for both transforma-
tions—simple reduction and reductive allylation—as depicted
in Scheme 2. The excited state [Ir(dtbbpy)(ppy)2]+* (or
[Ru(bpy)3]2+*) obtained upon visible-light irradiation of
[Ir(dtbbpy)(ppy)2]+ (or [Ru(bpy)3]2+) would be reductively
quenched by the Hantzsch ester to form the strong reductant
[Ir(dtbbpy)(ppy)2] (or [Ru(bpy)3]+). Single-electron transfer
to epoxychalcone 1a would then take place, thus regenerating
the iridium(III) (or ruthenium(II)) complex to provide the
radical anion 10. This radical anion would undergo ring
opening and either subsequent reduction by Hantzsch ester or
trapping by the allyl sulfone derivative.
Received: December 2, 2010
Revised: February 15, 2011
Published online: April 12, 2011
Keywords: allylation · aziridines · epoxides · photocatalysis ·
.
photoreduction
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2 equivalents of [Cp2TiCl] provides first epoxide ring opening
and formation of titanium enolates but without further func-
tionalization, see: C. Hardouin, F. Chevallier, B. Rousseau, E.
Doris, J. Org. Chem. 2001, 66, 1046 – 1048.
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