An official website of the United States government
Arynes hold immense potential as reactive intermediates in organic synthesis as they engage in a diverse range of mechanistically distinct chemical reactions. However, the poor functional group compatibility of generating arynes or their precursors has stymied their widespread use. Here, we show that generating arynes by deprotonation of an arene and elimination of an “onium” leaving group is mild, efficient and broad in scope. This is achieved by using aryl(TMP)iodonium salts (TMP = 2,4,6-trimethoxyphenyl) as the aryne precursor and potassium phosphate as the base, and a range of arynophiles are compatible. Additionally, we have performed the first quantitative analysis of functional group compatibility for several methods to generate arynes, including the method developed here and the current state of the art. Finally, we show that a range of “sensitive” functional groups such as Lewis and Brønsted acids and electrophiles are compatible under our conditions.
more »
« less
Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**
Abstract Herein, the synthesis of 1,2,3,4‐tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.[1]In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4‐tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post‐synthetic elaboration via palladium‐catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho‐ deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.
more »
« less
- Award ID(s):
- 1828573
- PAR ID:
- 10233440
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Chemistry – A European Journal
- Volume:
- 27
- Issue:
- 24
- ISSN:
- 0947-6539
- Page Range / eLocation ID:
- p. 7168-7175
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract We describe the development of a C–O coupling reaction between aryl(2,4,6-trimethoxyphenyl)iodonium salts and aliphatic alcohols under weak base conditions. The scope of the reaction is presented, with 16 examples ranging in yield from moderate to high (54–96%). The limitations of the reaction are also presented. Mechanistic experiments reveal a complex network of reactions that include side reactions that generate arynes and oxidize the alcohol nucleophile.more » « less
-
Aryl(Mes)iodonium salts, which are multifaceted aryl transfer reagents, are synthesized via boron-iodane exchange. Modification to both the nucleophilic (aryl boron) and electrophilic (mesityl–λ 3 –iodane) reaction components results in improved yield and faster reaction time compared to previous conditions. Mechanistic studies reveal a pathway that is more like transmetallation than S E Ar.more » « less
-
Phenol based aryliodonium salts were prepared by the reaction of [hydroxy(tosyloxy)iodo]arenes with aryl silyl ethers in the presence of trifluoromethanesulfonic acid. Structures of several aryliodonium salts with the hydroxy group in the para -position of the phenyl ring were established by single crystal X-ray crystallography. Under basic conditions, 4-hydroxyphenyl(phenyl)iodonium salts form a dimeric hypervalent iodine( iii ) complex, oxyphenyl(phenyl)iodonium ylidic salt, the solid structure of which was confirmed by X-ray crystallography. Phenolic iodonium salts are potentially useful phenol transfer reagents in reactions with various anionic nucleophiles.more » « less
-
Abstract Arynes are highly reactive and versatile intermediates for the functionalization of aromatic rings that are often generated using strong bases or fluoride sources, which, in some cases, can limit functional group tolerance. Here we demonstrate that triaryloxonium ions can be transformed into arynes through treatment with solid potassium phosphate at room temperature. A substantial range of functional group-bearing arynes, including 4,5-pyrimidynes, may be generated and trapped using cycloaddition reactions with high yields. Other arynophiles including nitrones, alkenes and azides are compatible with these conditions. Quantum computation in conjunction with an intramolecular kinetic isotope study is consistent with an elimination, unimolecular, conjugate base-like mechanism of elimination to form the aryne. These investigations demonstrate that the oxonium ion is a powerful electron-withdrawing group and a particularly effective leaving group. We anticipate that this study will stimulate further investigations into the synthetic utility of aryl oxonium ions.more » « less
