Photoinduced Copper-Catalyzed C-H Arylation at Room Temperature

Article abstract of DOI:10.1002/anie.201512027

Room-temperature azole C-H arylations were accomplished with inexpensive copper(I) compounds by means of photoinduced catalysis. The expedient copper catalysis set the stage for site-selective C-H arylations of non-aromatic oxazolines under mild reaction conditions, and provides step-economical access to the alkaloid natural products balsoxin and texamine. Copper light: Room-temperature C-H arylations of heteroarenes were accomplished with inexpensive copper compounds by photoinduced catalysis. The expedient copper catalysis leads to site-selective C-H arylations of non-aromatic oxazolines under mild reaction conditions, and provides step-economical access to the alkaloid natural products balsoxin and texamine.

Full text of DOI:10.1002/anie.201512027

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International Edition: DOI: 10.1002/anie.201512027
German Edition: DOI: 10.1002/ange.201512027
Photocatalysis
Hot Paper
À
Photoinduced Copper-Catalyzed C H Arylation at Room
Temperature
Fanzhi Yang, Julian Koeller, and Lutz Ackermann*
Dedicated to Professor Jochen Mattay
À
Abstract: Room-temperature azole C H arylations were
accomplished with inexpensive copper(I) compounds by
means of photoinduced catalysis. The expedient copper
catalysis, on which we report herein. Notable features of our
approach include a) photoinduced base-metal[18] catalysis for
À
À
C H activation, b) copper-catalyzed C H arylations at room
catalysis set the stage for site-selective C H arylations of
temperature, c) ligand acceleration by amino acids[19] in
À
À
non-aromatic oxazolines under mild reaction conditions, and
provides step-economical access to the alkaloid natural
products balsoxin and texamine.
photoinduced C H activation, and d) versatile copper cata-
lysts that proved effective for aromatic azole and nonaromatic
oxazoline substrates—key structural motifs of chiral
ligands[20] and natural products (Figure 1).
À
C
atalyzed C H activation has emerged as a power-
ful platform for the step-economical diversification
of heteroarenes.[1] Particular progress in C H acti-
À
vation chemistry was accomplished using earth-
abundant copper catalysts,[2] with early contributions
À
to copper(I)-catalyzed C H arylations by the groups
of Daugulis,[3] Miura,[4] and Gaunt,[5] as well as
Ackermann[6] among others.[2] Despite these undis-
À
puted advances, copper(I)-catalyzed C H arylations
À
Figure 1. Photoinduced copper-catalyzed C H activation.
with easily accessible aryl halides continue to face
major limitations in that they require rather harsh
reaction conditions with typical reaction temper-
atures ranging from 120 to 1608C.
We initiated our studies by probing reaction conditions for
In recent years, photocatalysis[7] has been recognized as an
increasingly viable tool to realize one-electron-transfer cross-
coupling reactions, with key contributions by the groups of
Reiser,[8] Kçnig,[9] and Glorius,[10] among others.[11–14] The
photocatalysis reaction manifold was also merged with pre-
the envisioned C H activation on the substrate 1a by using
photoinduced copper catalysis (Table 1; and see Tables S-
1 and S-2 in the Supporting Information).[21] Preliminary
experiments revealed CuI and Et2O to be the catalyst and
solvent of choice, respectively (entries 1–5). While the photo-
À
À
À
cious second-row transition-metal C H activation catalysts,
assisted C H arylation occurred under ligand-free reaction
such as palladium, ruthenium, and rhodium complexes, as
elegantly elaborated by among others Sanford[15] and Ruep-
ing,[16] exploiting entropically favored intramolecular reac-
tions[16c] or Lewis-basic directing groups.[15,16a,b] In contrast,
photoinduced copper-catalyzed
conditions (entries 4–6), here a higher catalyst loading was
required to ensure a satisfactory performance (entry 5).
Among a set of representative ligands, a significant rate
acceleration was exerted by amino acid derivatives (entries 7–
12), and the best results were obtained with the aid of N,N-
dimethylglycine (entries 11 and 12). Control experiments
confirmed the essential role of the copper catalyst (entry 13),
and unambiguously illustrated the photocatalytic nature of
À
C H arylations with organic halides have thus far proven
À
elusive. Within our program on sustainable C H activation by
base-metal catalysis,[17] we have now devised a protocol for
À
À
unprecedented photoinduced C H arylation by copper(I)
the C H functionalization process (entry 14).
With the optimized reaction conditions in hand, we tested
À
the versatility of the photoassisted C H arylation with
benzannulated heteroarenes 1 (Scheme 1). Thus, the broadly
[*] Dr. F. Yang, J. Koeller, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
À
applicable copper(I) catalyst enabled efficient C H function-
alizations of benzothiazoles and benzoxazoles 1 which were
devoid of directing groups. The chemoselectivity of the robust
catalyst was reflected by its tolerance of valuable functional
groups, such as chloro or ester substituents.
The versatile copper catalyst was not limited to the
benzannulated substrates 1. Indeed, the azoles 4 bearing
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
Prof. Dr. L. Ackermann
International Center for Advanced Studies of Energy Conversion
(ICASEC), Georg-August University of Gçttingen (Germany)
À
various aromatic C H bonds proved to be amenable for site-
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201512027.
À
selective C H arylations (Scheme 2a). Hence, we were
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[a]
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Table 1: Validation of photoinduced copper-catalyzed C H arylation.
Entry
Ligand
Solvent
Yield [%][b]
1
2
3
4
5
6
–
–
–
–
–
–
DMA
1,4-dioxane
THF
Et2O
Et2O
37[c,d]
10[d,e]
30[d,e]
48[d]
80[f]
57
Et2O
7
TMEDA
Et2O
36
8
bpy
Et2O
39
9
l-Pro-OH
l-Ala-OH
Me2NCH2CO2H
Me2NCH2CO2H
Me2NCH2CO2H
Me2NCH2CO2H
Et2O
Et2O
62
67
67
10
11
12
13
14
Et2O
Et2O[g]
Et2O
73
0[h]
Et2O
0[i]
[a] Reaction conditions: 1a (0.25 mmol), 2a (1.25 mmol), CuI (20 mol
%), ligand (30 mol %), 254 nm, LiOtBu (0.75 mmol), Et2O (1.5 mL).
[b] Yield of isolated product. [c] 508C. [d] CuI (10 mol %). [e] Conversion
determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as
the internal standard. [f] CuI (50 mol %). [g] Et2O (1.0 mL). [h] Without
CuI. [i] In the dark. bpy=4,4’-bipyridine, DMA=N,N-dimethyl acet-
amide, RT=room temperature (25–278C),[21] THF=tetrahydrofuran,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
À
Scheme 2. Photoinduced C H arylation of azoles 4. a) Scope with
respect to azoles 4. b) Synthesis of alkaloids.
of copper compounds at 1608C,[24] thus reflecting the unique
potential of the photoinduced copper-catalysis approach.
À
Accomplishing C H arylations of non-aromatic sub-
strates is difficult, because these substrates lack the aromatic
moiety which engages in attractive interactions with the
transition metal.[25] Hence, we were particularly delighted to
À
observe that the photoinduced copper(I)-catalyzed C H
arylation strategy proved applicable to the diversification of
non-aromatic oxazolines 6 (Scheme 3), which are important
structural motifs in various chiral ligands.[20] It is noteworthy
that the inexpensive photoinduced copper catalysis compares
À
favorably with the previously reported C H arylation of
oxazolines (6) by expensive palladium catalysts at a reaction
temperature of 1008C.[26] Moreover, our approach is comple-
mentary to outer-sphere radical-based catalysts, which target
À
Scheme 1. Photoinduced copper-catalyzed C H arylation of benzoxa-
zoles 1.
delighted to observe that a set of differently decorated
thiazoles, oxazoles, and oxadiazoles 4a–f was converted with
comparable catalytic efficacy. It is particularly noteworthy
À
that the photoinduced C H arylation strategy provided step-
economical access to the alkaloid natural products balsoxin
(5gb) and texamine (5hb)[22] at room temperature (Sche-
me 2b). Thus far, the syntheses of these natural products by
À
C H functionalization technology largely called for either
palladium or nickel catalysts, typically at reaction temper-
À
Scheme 3. Photoinduced copper-catalyzed C H arylation of non-aro-
matic oxazolines 6.
atures between 120 and 1508C,[23] or stoichiometric amounts
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the weakest benzylic C H bond in proximity to the nitrogen
atom in the substrates 6b,c.
for photoinduced copper catalysis, which set the stage for the
efficient synthesis of the naturally occurring alkaloids bal-
À
À
Interestingly, the photoassisted C H arylation could be
achieved by using visible light (Scheme 4), provided that an
soxin and texamine by room-temperature C H arylation.
Acknowledgements
Generous support by the European Research Council under
the European Communityꢀs Seventh Framework Program
(FP7 2007-2013)/ERC Grant agreement no. 307535, and the
Chinese Scholarship Program (fellowship to F.Y.) is gratefully
acknowledged.
À
Scheme 4. Visible-light photoredox-catalyzed C H arylation.
À
iridium photoredox catalyst was employed in a hetero-
bimetallic cooperative catalysis regime (see Table S-3).
Given the versatility of the photoinduced copper-cata-
Keywords: alkaloids · C H activation · copper · photocatalysis ·
total synthesis
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Angew. Chem. 2016, 128, 4837–4840
À
lyzed C H arylation, we became intrigued by performing
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tially converted (Scheme 5), thereby rendering an oxidative
À
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À
À
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À
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Received: December 30, 2015
Revised: January 29, 2016
Published online: March 9, 2016
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