For bioactive molecules, bicyclo[1.1.1]pentanes (BCPs) are an emerging isostere of rigid spacer groups that have shown potential to improve drug‐like qualities. As BCPs become an increasingly popular motif for evaluation in drug candidates, organic chemists must meet the demand to reliably incorporate them into new targets. To provide access to BCP analogues of diaryl methanamines, a ubiquitous scaffold in medicinal chemistry, we report the synthesis of BCP benzylamines through reactivity of [1.1.1]propellane with 2‐azaallyl anions, which are generated in situ from
For bioactive molecules, bicyclo[1.1.1]pentanes (BCPs) are an emerging isostere of rigid spacer groups that have shown potential to improve drug‐like qualities. As BCPs become an increasingly popular motif for evaluation in drug candidates, organic chemists must meet the demand to reliably incorporate them into new targets. To provide access to BCP analogues of diaryl methanamines, a ubiquitous scaffold in medicinal chemistry, we report the synthesis of BCP benzylamines through reactivity of [1.1.1]propellane with 2‐azaallyl anions, which are generated in situ from
- NSF-PAR ID:
- 10078601
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 57
- Issue:
- 48
- ISSN:
- 1433-7851
- Page Range / eLocation ID:
- p. 15857-15861
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Abstract N ‐benzyl ketimines. The reaction proceeds rapidly at room temperature and tolerates a broad substrate scope, providing straightforward access to 23 new BCP benzylamine derivatives. Initial experiments support the intermediacy of a BCP anion. Additionally, the reaction can be promoted by substoichiometric loadings of base, highlighting an unusual reactivity of both 2‐azaallyls and [1.1.1]propellane. -
null (Ed.)We report a 3-component reaction between N -benzyl ketimines, [1.1.1]propellane, and pinacol boronates to generate benzylamine bicyclo[1.1.1]pentane (BCP) pinacol boronates. These structures are analogous to highly sought diarylmethanamine cores, which are common motifs in bioactive molecules. We demonstrate the versatility of the boronate ester handle via downstream functionalization through a variety of reactions, including a challenging Pd-catalyzed (hetero)arylation that exhibits a broad substrate scope. Together, these methods enable the synthesis of high-value BCP benzylamines which are inaccessible by existing methods. Furthermore, we demonstrate the successful application of these newly developed (hetero)arylation conditions to a variety of challenging tertiary pinacol boronates, including nitrogen-containing heterocycles, 1,1-disubstituted cyclopropanes, and other BCP cores.more » « less
-
more » « less
Abstract Controlling the self‐assembly behaviors of block copolymers (BCPs) is a focal point of many research thrusts due to their broad use in various applications. While BCP molecular weight, volume fraction, and chemical identities are key thermodynamic parameters to determine their morphology, an emergent method in this area is through reaction‐induced changes to the characteristics of a BCP
in situ , which provides access to multiple morphologies and domain sizes from a single parent polymer, as well as enabling the formation of metastable morphologies which may be difficult to attain otherwise. This work provides a focused review about the current state of reaction‐induced morphology control in BCPs in both solution and solid states. Furthermore, we provide a forward‐looking perspective on the future opportunities of understanding and employing reaction engineering to manipulate and advance BCP self‐assembly. © 2023 Society of Industrial Chemistry. -
more » « less
ABSTRACT Herein, we report the design and synthesis of a block copolymer (BCP) with a high Flory–Huggins interaction parameter to access 10 nm feature sizes for potential lithographic applications. The investigated BCP is poly[(2‐methyl‐2‐oxazoline)‐
block ‐styrene] (PMeOx‐b ‐PS), where the PMeOx segment functions as a hydrophilic segment. Two BCPs with different molecular weights were prepared using PMeOx as macroinitiator for copper(0) mediated controlled radical polymerization. The thin film self‐assembly of the obtained PMeOx‐b‐ PS was performed by solvent annealing and investigated by atomic force microscopy. Both polymers formed PMeOx cylinders in a PS matrix with an average cylinder diameter of 10.5 nm. Additionally, the ability of the PMeOx domains to selectively degrade under ultraviolet irradiation was explored. It was shown that scission of the PMeOx block does occur selectively, and furthermore that the degraded domains can be removed while leaving the PS matrix intact. By combining synthetic accessibility, small feature sizes, and a selectively cleavable domain, this new BCP system holds significant promise as a lithographic mask for patterning surfaces with high precision. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1349–1357 -
more » « less
Abstract A catalyst‐ and additive‐free decarbonylative trifluoromethylthiolation of aldehyde feedstocks has been developed. This operationally simple, scalable, and open‐to‐air transformation is driven by the selective photoexcitation of electron donor‐acceptor (EDA) complexes, stemming from the association of 1,4‐dihydropyridines (donor) with
N ‐(trifluoromethylthio)phthalimide (acceptor), to trigger intermolecular single‐electron transfer events under ambient‐ and visible light‐promoted conditions. Extension to other electron acceptors enables the synthesis of thiocyanates and thioesters, as well as the difunctionalization of [1.1.1]propellane. The mechanistic intricacies of this photochemical paradigm are elucidated through a combination of experimental efforts and high‐level quantum mechanical calculations [dispersion‐corrected (U)DFT, DLPNO‐CCSD(T), and TD‐DFT]. This comprehensive study highlights the necessity for EDA complexation for efficient alkyl radical generation. Computation of subsequent ground state pathways reveals that SH2 addition of the alkyl radical to the intermediate radical EDA complex is extremely exergonic and results in a charge transfer event from the dihydropyridine donor to theN ‐(trifluoromethylthio)phthalimide acceptor of the EDA complex. Experimental and computational results further suggest that product formation also occursvia SH2 reaction of alkyl radicals with 1,2‐bis(trifluoromethyl)disulfane, generated in‐situ through combination of thiyl radicals.magnified image
