Cinnamylamines make-up many important drugs that target G protein-coupled receptors. While 3,3-diarylallylamines can be prepared via existing synthetic methods, these often require poorly-selective Wittig addition to unsymmetrical ketones, and multistep sequences thereafter to reach the allylamine product. Methods that make use of direct aryl addition to N -protected cinnamylamines via a Mizoroki–Heck pathway are known, however, unprotected cinnamylamines are sensitive to a mixture of C–H activation and Mizoroki–Heck arylation under Pd-catalysed arylation conditions using aryl iodides. This leads to a decrease in the trans / cis selectivity that can be achieved under these reaction conditions. By reimagining the reaction and using aryl boronic acids, we have herein demonstrated how in many cases the yield and E / Z selectivity can be improved. The in situ -formed active catalyst is more sensitive under these conditions, and was observed to shut down at elevated temperatures.
more »
« less
Precise electrical gating of the single-molecule Mizoroki-Heck reaction
Abstract Precise tuning of chemical reactions with predictable and controllable manners, an ultimate goal chemists desire to achieve, is valuable in the scientific community. This tunability is necessary to understand and regulate chemical transformations at both macroscopic and single-molecule levels to meet demands in potential application scenarios. Herein, we realise accurate tuning of a single-molecule Mizoroki-Heck reaction via applying gate voltages as well as complete deciphering of its detailed intrinsic mechanism by employing an in-situ electrical single-molecule detection, which possesses the capability of single-event tracking. The Mizoroki-Heck reaction can be regulated in different dimensions with a constant catalyst molecule, including the molecular orbital gating of Pd(0) catalyst, the on/off switching of the Mizoroki-Heck reaction, the promotion of its turnover frequency, and the regulation of each elementary reaction within the Mizoroki-Heck catalytic cycle. These results extend the tuning scope of chemical reactions from the macroscopic view to the single-molecule approach, inspiring new insights into designing different strategies or devices to unveil reaction mechanisms and discover novel phenomena.
more »
« less
- NSF-PAR ID:
- 10412547
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 13
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
more » « less
Abstract The Mizoroki–Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Given its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that allows a Heck reaction to occur at a specific nonfunctionalized C(sp3)−H site is desirable. Reported here is a radical relay Heck reaction which allows selective remote alkenylation of aliphatic alcohols at unactivated β‐, γ‐, and δ‐C(sp3)−H sites. The use of an easily installed/removed Si‐based auxiliary enables selective I‐atom/radical translocation events at remote C−H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible‐light‐mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks.
-
more » « less
Abstract The Mizoroki–Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Given its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that allows a Heck reaction to occur at a specific nonfunctionalized C(sp3)−H site is desirable. Reported here is a radical relay Heck reaction which allows selective remote alkenylation of aliphatic alcohols at unactivated β‐, γ‐, and δ‐C(sp3)−H sites. The use of an easily installed/removed Si‐based auxiliary enables selective I‐atom/radical translocation events at remote C−H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible‐light‐mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks.
-
The synthesis of a new Nile red derivative incorporating a reactive aldehyde moiety (NR-CHO) is reported and its use in spectroscopic studies of heterogeneous catalyst activity in crossed aldol reactions is demonstrated. 1 H and 13 C NMR, and high-resolution mass spectrometry confirmed the desired NR-CHO was obtained. Mg-Zr-Cs doped silica (Cs(Zr,Mg)-SiO 2 ) was employed as the catalyst and its performance was compared to that of commercially available MgO. Fumed silica was used as a control. Aldol reactions with acetone and acetophenone were run in 4 : 1 (v/v) DMSO : ketone solutions in the presence of both dilute (1 μM) and concentrated (1 mM) NR-CHO. NR-CHO fluorescence spectra were acquired as the reactions progressed. Shifts in its emission spectrum are used to distinguish the products formed and to characterize the reaction rate. The dye exhibits different behavior that defines whether the reaction stops at the addition (alcohol) product, or forms both addition and condensation (olefin) products, providing valuable initial information on catalyst activity. The assignment of addition and condensation products is supported by thin layer chromatography, high performance liquid chromatography (HPLC), and HPLC-mass spectrometry data. Product formation is shown to depend upon the catalyst employed, with the Cs(Zr,Mg)-SiO 2 yielding both addition and condensation products, while MgO yields primarily addition products. The advantages of NR-CHO in spectroscopic studies of aldol reactions are also demonstrated relative to commercially available 3-perylenecarboxaldehyde. The NR-CHO reported here and the results obtained will facilitate a broad range of both ensemble and single molecule spectroscopic investigations of heterogeneous catalysis in crossed aldol reactions in the future.more » « less
-
The transition metal-catalyzed Mizoroki–Heck reaction is a powerful method to synthesize C–C bonds, allowing access to several important pharmaceuticals. Traditionally free amines have not been compatible with these approaches due to oxidation of the amine by the transition metal or other side reactions. However, the functionalization of unprotected allylamines is particularly attractive due to their prevalence in various biologically active molecules. Herein we report the palladium-catalyzed selective monoarylation of free allylamines using aryl iodides. The strategy works on primary, secondary, and tertiary amines, making it very general. Our monoarylation method is scalable and works on aryl iodides with a variety of substituted arene or heterocycle motifs, including chromophoric substrates.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41467-022-32351-8
