Xiaoqiang
Huang‡
a,
Shipeng
Luo‡
a,
Olaf
Burghaus
a,
Richard D.
Webster
b,
Klaus
Harms
a and
Eric
Meggers
*a
aFachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany. E-mail: meggers@chemie.uni-marburg.de
bDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
First published on 1st September 2017
We report an unusual reaction design in which a chiral bis-cyclometalated rhodium(III) complex enables the stereocontrolled chemistry of photo-generated carbon-centered radicals and at the same time catalyzes an enantioselective sulfonyl radical addition to an alkene. Specifically, employing inexpensive and readily available Hantzsch esters as the photoredox mediator, Rh-coordinated prochiral radicals generated by a selective photoinduced single electron reduction are trapped by allyl sulfones in a highly stereocontrolled fashion, providing radical allylation products with up to 97% ee. The hereby formed fragmented sulfonyl radicals are utilized via an enantioselective radical addition to form chiral sulfones, which minimizes waste generation.
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Fig. 1 Visible-light-activated asymmetric transformations with allylic C(sp2) radical intermediates. |
Herein, we demonstrate that a rhodium-based Lewis acid bearing exclusive metal-centered chirality can effectively control the stereochemistry of visible-light-generated prochiral radicals for the asymmetric radical allylation reaction with allyl sulfones as radical traps (Fig. 1d). Notably, the leaving sulfonyl radicals can be utilized providing β-sulfonyl carbonyl compounds which is without precedence in the chemistry of these well-developed sulfone-based radical trap reagents.11,12
Two key challenges are needed to be solved to achieve a high asymmetric induction. Firstly, a robust and effective chiral Lewis acid catalyst is required to control the stereochemistry of two mechanistically distinct processes as well as reduce the reduction potential of substrate 1 to ensure a highly chemoselective reduction. Secondly, the radical trapping and subsequent fragmentation process should be fast enough to compete with the protonation of intermediate B which would generate undesirable free β-carbonyl carbon radicals. The reaction of such free radicals with 2 would compromise the enantioselectivity of product 3. Therefore, this design with the utilization of the leaving sulfonyl radicals, which otherwise would lead to by-products, is very attractive not only from the perspective of green and sustainable chemistry17 but also for suppressing side reactions of the sulfonyl radical and shifting the equilibrium of a potentially reversible radical fragmentation.11
Entry | Lewis acidb | HE | 3a | 4a | ||
---|---|---|---|---|---|---|
Yieldc (%) | eed (%) | Yieldc (%) | eed (%) | |||
a Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), Lewis acid and Hantzsch ester (0.15 mmol) in 1,4-dioxane (1.0 mL) were stirred at room temperature for 24 h and irradiated with a 21 W CFL. b Loadings in mol% provided in brackets. c Isolated yields. d Determined by HPLC on a chiral stationary phase. e 0.15 mmol of N,N-diisopropylethylamine (DIPEA) was employed. f Blue LEDs (24 W) were used instead of a CFL (21 W). g Performed in darkness. n.a. = not applicable. | ||||||
1 | Δ-IrS (8.0) | HE-1 | <5 | n.a. | <5 | n.a. |
2 | Δ-RhS (8.0) | HE-1 | 92 | 83 | 95 | 84 |
3 | Δ-RhO (8.0) | HE-1 | 85 | 96 | 92 | 85 |
4 | Sc(OTf)3 (20) | HE-1 | 10 | n.a. | 10 | n.a. |
5 | LiBF4 (200) | HE-1 | 0 | n.a. | 0 | n.a. |
6 | None | HE-1 | 0 | n.a. | 0 | n.a. |
7 | Δ-RhO (8.0) | HE-2 | 78 | 96 | 82 | 80 |
8 | Δ-RhO (8.0) | HE-3 | 80 | 94 | 85 | 85 |
9e | Δ-RhO (8.0) | None | 0 | n.a. | 0 | n.a. |
10f | Δ-RhO (8.0) | HE-1 | 77 | 92 | 80 | 80 |
11g | Δ-RhO (8.0) | HE-1 | 0 | n.a. | 0 | n.a. |
With the optimized conditions at hand, we next investigated the substrate scope with respect to radical acceptors (Table 2). A wide range of allyl sulfones 2 with different leaving groups works well, delivering the radical allylation product 3a in good yields and excellent ee (up to 97% ee) along with the recycled C–S formation products 4a–h in good yields and ee (up to 89% ee) (entries 1–8). Intriguingly, a lower yield and slightly lower ee were observed for the radical functionalization product 3b when allyl sulfone bearing a less electron deficient ester group was employed (compare entries 9 with 1). It is noteworthy that functional groups including a CC triple bond, a C
C double bond and an imide are well tolerated under these mild conditions (entries 11–13). As a limitation, substrates with a long chain at the β-position (1b–d) produced the radical allylation products 3f–h with decreased ee (eqn (1)) and β-aryl α,β-unsaturated N-acylpyrazole could not afford any expected product. Furthermore, the alkenyl sulfone 5 was proven to be competent, providing the radical alkenylation product 6 in 54% yield with 93% ee (eqn (2)).
Entry | EWG | Ar | 3, Yieldb, eec | 4, Yieldb, eec |
---|---|---|---|---|
a Reaction conditions: 1a (0.20 mmol), 2 (0.10 mmol), Δ-RhO (0.008 mmol) and HE-1 (0.15 mmol) in 1,4-dioxane (1.0 mL) were stirred at room temperature and irradiated with a 21 W CFL. b Isolated yields. c Determined by HPLC on a chiral stationary phase. d 35 °C. | ||||
1 | CN | C6H5 | 3a, 85%, 96% ee | 4a, 92%, 85% ee |
2 | CN | 4-MeC6H4 | 3a, 68%, 96% ee | 4b, 70%, 79% ee |
3 | CN | 4-BrC6H4 | 3a, 81%, 97% ee | 4c, 88%, 80% ee |
4 | CN | 4-CF3C6H4 | 3a, 78%, 95% ee | 4d, 78%, 76% ee |
5 | CN | 2-MeC6H4 | 3a, 71%, 95% ee | 4e, 72%, 86% ee |
6d | CN | 2,4,6-Me3C6H2 | 3a, 57%, 94% ee | 4f, 60%, 89% ee |
7d | CN | 2-Naphthyl | 3a, 82%, 94% ee | 4g, 88%, 83% ee |
8d | CN | 1-Naphthyl | 3a, 78%, 91% ee | 4h, 84%, 80% ee |
9 | COOEt | C6H5 | 3b, 65%, 94% ee | 4a, 68%, 84% ee |
10d | COOEt | 4-MeOC6H4 | 3b, 65%, 92% ee | 4i, 63%, 81% ee |
11d |
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C6H5 | 3c, 60%, 92% ee | 4a, 69%, 82% ee |
12d |
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C6H5 | 3d, 62%, 92% ee | 4a, 72%, 83% ee |
13d |
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C6H5 | 3e, 73%, 92% ee | 4a, 78%, 82% ee |
![]() | (1) |
![]() | (2) |
To further evaluate the functional group tolerance and robustness of this catalytic system, we conducted the reaction 1a + 2a → 3a + 4a in the presence of a series of common chemical functionalities (Table 3 and ESI†).20 To our satisfaction, this reaction shows a high chemo-selectivity towards the Lewis acid coordinated substrate (intermediate A) as additives containing azido, cyano, and carbonyl groups that are vulnerable to reductive conditions can be recovered in high yields under the standard conditions (entries 1–4). Importantly, several heterocycles which might competitively coordinate to the catalyst did not erode the enantiomeric excess of products (entries 3–9). Several natural products, including coumarin, caffeine, and (−)-citronellol, were found to have little influence on the reaction outcomes (entries 7–10). Furthermore, N-acylpyrazoles known as a useful and reactive synthetic building block can be easily converted into other compounds, such as alcohols or amides (eqn (3) and (4)). Overall, these results highlight the potential of this protocol for further applications in the synthesis of complex molecules.
Entry | Additive | Additive recoveredb | (R)-3a | (S)-4a | ||
---|---|---|---|---|---|---|
Yieldb | eec | Yieldb | eec | |||
a Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), Λ-RhO (0.008 mmol), HE-1 (0.15 mmol) and additives (0.10 mmol) in 1,4-dioxane (1.0 mL) were stirred at room temperature for 24 h and irradiated with a 21 W CFL. b Isolated yields. c Determined by HPLC on a chiral stationary phase. | ||||||
1 |
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88% | 86% | 96% ee | 85% | 86% ee |
2 |
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94% | 86% | 96% ee | 85% | 83% ee |
3 |
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99% | 86% | 96% ee | 92% | 83% ee |
4 |
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88% | 82% | 96% ee | 88% | 83% ee |
5 |
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95% | 86% | 95% ee | 92% | 85% ee |
6 |
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99% | 86% | 96% ee | 85% | 83% ee |
7 |
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96% | 82% | 96% ee | 92% | 85% ee |
8 |
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99% | 82% | 95% ee | 92% | 83% ee |
9 |
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99% | 86% | 96% ee | 92% | 85% ee |
10 |
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94% | 86% | 96% ee | 92% | 85% ee |
![]() | (3) |
![]() | (4) |
A number of experiments support the proposed mechanism (Fig. 2). Firstly, UV/vis spectra and luminescence spectra support the role of the HE as a visible light harvesting antenna being consistent with recent reports (Fig. S3 in ESI†).15 Secondly, Stern–Volmer quenching experiments demonstrate that the rhodium coordinated substrate RhO-1a21 but not the free substrates 1 or 2 can effectively quench the luminescence of HE-1, suggesting that a selective SET process between the photoexcited HE* and intermediate A might occur (Fig. S4 and S5 in ESI†). This is further confirmed by cyclic voltammetry, in which a large difference in the reduction peak potential by almost 1 V was observed between 1a (−2.59 V vs. Fc/Fc+) and RhO-1a (−1.62 V vs. Fc/Fc+), thus making highly selective SET between RhO-1a and the excited state of HE-1 (E(HE˙+/HE*) = −2.23 V vs. Fc/Fc+) feasible (Fig. S6 in ESI†). Furthermore, the title reaction was greatly inhibited upon adding 2,6-di-tert-4-methylphenol (BHT) or 2,2,6,6-tetramethyl-piperidinooxy (TEMPO) as radical scavengers. When the reaction was monitored by electron paramagnetic resonance (EPR) using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a free radical spin-trapping agent, mixed signals containing two radical species were observed, one of which was identified as a phenyl sulfonyl radical (g = 2.006, αN = 9.5 G, αβH = 12.9 G) (Fig. S8 in ESI†).22 Finally, a quantum yield of 0.09 was determined for the reaction 1a + 2a → 3a + 4a, which is consistent with the proposed mechanism being devoid of any chain process (see ESI for details†).
Footnotes |
† Electronic supplementary information (ESI) available: Characterization data and experimental procedures. CCDC 1547314–1547316. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc02621h |
‡ These authors contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2017 |