1,4,2-Dioxazol-5-ones are known to undergo decarboxylation under thermal conditions followed by Lossen’s rearrangement to give isocyanates. Described herein is the in situ trapping of the isocyanates by indoles to give indole-3-carboxamides in good to excellent yields.
The mechanically induced symmetry-allowed disrotatory ring openings of cis- and trans-gem-dichlorocyclopropane (gDCC) diesters are demonstrated through sonication and single-molecule force spectroscopy (SMFS) studies. In contrast to the previously reported symmetry-forbidden conrotatory ring opening of alkyl-tethered trans-gDCC, we show that the diester-tethered trans-gDCC primarily undergoes a symmetry-allowed disrotatory pathway even at the high forces (>2 nN) and short-time scales (ms or less) of sonication and SMFS experiments. The quantitative force-rate data obtained from SMFS data is consistent with computational models of transition-state geometry for the symmetry-allowed process, and activation lengths of 1.41 ± 0.02 Å and 1.08 ± 0.03 Å are inferred for the cis-gDCC diester and trans-gDCC diester, respectively. The strong mechanochemical coupling in the trans-gDCC is notable, given that the directionality of the applied force may appear initially to oppose the disrotatory motion associated with the reaction. The stereochemical perturbations of mechanical coupling created by the ester attachments reinforce the complexity that is possible in covalent polymer mechanochemistry and illustrate the breadth of reactivity outcomes that are available through judicious mechanophore design.
Palladium-catalyzed direct arylation of α,β-unsaturated carbonyl compounds is an efficient and attractive strategy to access arylated α,β-unsaturated carbonyl compounds through the construction of carbon–carbon bonds. This reaction has several challenges, especially in terms of the control of regioselectivity between α- and γ-arylation and the selectivity for monoarylation and multiple arylation. Herein, we discuss the recent development of γ-arylation of α,β-unsaturated carbonyl compounds and present the ligand-controlled, site-selective α- and γ-arylation of α,β-unsaturated carbonyl ketones with (hetero)aryl halides. The site selectivity of the reaction is switchable by simply changing the phosphine ligand.1 Introduction2 Reaction Development and Mechanistic Investigation3 Conclusion and Outlook
C–H activation of functionally rich molecules without the need for directing groups promises shorter organic syntheses and late-stage diversification of molecules for drug discovery. We highlight recent examples of palladium-catalyzed nondirected functionalization of C–H bonds in arenes as limiting substrates with a focus on the development of the concept of spatial anion control for direct C–H arylation.1 C–H Activation and the CMD Mechanism2 Nondirected C–H Functionalizations of Arenes as Limiting Substrates3 Nondirected C–H Arylation4 Spatial Anion Control for Direct C–H Arylation5 Coordination Chemistry with Spatial Anion Control6 Conclusion
C-Alkyl glycosides represent an attractive class of nonhydrolyzable carbohydrate mimetics which possess enormous potential as next-generation therapeutics. Methods for the direct stereoselective synthesis of C-alkyl glycosides with a broad substrate tolerance are limited, however. This is especially in the case of β-linked C-alkyl glycosides, where direct methods for synthesis from commonly available coupling partners remain limited. This Account describes the evolution of our laboratory’s studies on glycosyl sulfonate chemistry from a method for the construction of simple β-linked 2-deoxy-sugars to a technology for the direct synthesis of β-linked acyl and homoacyl glycosides that can be elaborated into more complex structures.1 Introduction2 Glycosyl Sulfonates3 Glycosyl Sulfonates in Oligosaccharide Synthesis4 Matching Donor and Sulfonate Reactivity5 β-Linked C-Acyl and Homoacyl Glycoside Synthesis6 Elaboration to other Products7 Conclusion
We report a simple protocol for (ethoxycarbonyl)difluoromethylthiolation of nucleophilic compounds using a difluoroalkyl sulfonium salt which can be prepared in situ via Tf2O-triggered electrophilic activation of a benzyl difluoroalkyl sulfoxide. With the protocol, difluoroalkylthiolated arenes, heteroarenes, α-difluoroalkylthiolated carbonyl compounds, etc. were obtained smoothly with good to excellent yields. Merits of the reaction include the readily available difluoroalkylthiolation reagent and substrates, mild conditions, and excellent regioselectivity.
Reductive radical cyclizations are ubiquitous in organic synthesis and have been applied to the synthesis of structurally complex molecules. N-Heterocyclic motifs can be prepared through the cyclization of α-haloamides; however, slow rotation around the amide C–N bond results in preferential formation of an acyclic hydrodehalogenated product. Here, we compare four different methods for preparing γ-, δ-, ε-, and ζ-lactams via radical cyclization. We found that a photoenzymatic method using flavin-dependent ‘ene’ reductases affords the highest level of product selectivity. We suggest that through selective binding of the cis-amide isomer, the enzyme preorganizes the substrate for cyclization, helping to avoid premature radical termination.
A cascade reaction of 3-phenacylideneoxindoles with trimethylsilyl cyanide is described. This method provides an efficient route for the synthesis of furan-fused 1,3-benzodiazepin-2-one derivatives by simply refluxing a reaction mixture of various 3-phenacylideneoxindoles with trimethylsilyl cyanide in the presence of H2O and K2CO3.
A new general process for constructing ortho-tert-butyl phenols is presented within the context of other known methods. All are briefly evaluated with regards to regioselectivity, efficiency, and functional group tolerance. In addition, we present an assortment of tert-butyl substrates accessed through o-QM chemistry. Our conclusion is that the o-QM process provides greater yields, flexibility, and generality than most other known methods for delivering ortho-tert-buytlated phenols and their derivatives.1 Introduction2 Friedel–Crafts Alkylation3 Addition of t-Bu– or t-Bu• to Carbonyl Compounds4 ipso-SNAr Reactions of Aryl Methoxy and tert-Butylsulfoxide Moieties5 Metal-Mediated Coupling of Aryl Bromides6 Applications of o-Quinone Methides (o-QMs)7 Conclusion
Polyampholyte hydrogels have shown promise as functional biomaterial platforms with resistance to nonspecific protein adsorption (nonbiofouling). Yet there are few zwitterionic cross-linkers available to complement these materials and to provide an extended charge density throughout the 3D network. The recent development of peptide-based zwitterionic cross-linkers has shown merit. Indeed, the use of functionalizable amino acids permits the synthesis of a series of peptide-based zwitterionic methacrylate and methacrylamide cross-linkers. Methacrylate additions prior to peptide coupling provide an outside-in strategy when using natural l-serine or l-lysine as substrates to produce a series of methacrylate and methacrylamide combinations, expanding the library of peptide-based cross-linkers. Here, we describe the preparation of such dipeptide combinations as Ser-Lys, Lys-Ser, and Lys-Lys in zwitterionic bis(methacrylate/methacrylamide) cross-linkers. To highlight the utility of this method and its potential to increase the distance between zwitterionic components, syntheses of the tripeptide Lys-Gly-Lys dimethacrylamide and Ser-Gly-Ser dimethacrylate are reported.