Convenient Access to Chiral Cyclobutanes with Three Contiguous Stereocenters from Verbenone by Directed C(sp³)−H arylation

Abstract

This work demonstrates how a series of complex, chiral cyclobutane derivatives can be accessed in four steps from the terpene verbenone through the application of a directed C−H functionalization approach. The developed synthetic route involved an 8‐aminoquinoline‐directed C(sp3)−H arylation as the key step, and this reaction could be carried out with a wide range of aryl and heteroaryl iodides to furnish a variety of cyclobutane products with three contiguous stereocenters. Moreover, it was shown that the 8‐aminoquinoline auxiliary could be effectively removed from the cyclobutane derivatives using an ozonolysis‐based cleavage method.

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives Through a Combination of 8-Aminoquinoline Directed C–H Arylations and Transamidations

“…Furthermore, Ag2CO3 proved to be an inferior silver source compared to AgOAc, allowing product 2a to only be obtained in 49% yield after 7 h (See SI, Table S1). However, we were delighted to see that the model C-H arylation reaction could be further improved through change of solvent (Entries [12][13][14][15][16]. The green solvents tert-amyl-OH, methyl-THF and CPME all showed to be better alternatives than toluene for this transformation (Entries 12-14 vs Entry 9).…”

“…SiliaSep SiO2 cartridges used for these purifications were obtained from SiliCycle. 1 H and 13 C NMR spectra were recorded on Bruker Avance-II instruments at 400 MHz (H) and at 100 MHz (C), respectively. Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCl3 (δ(H)= 7.26 and δ(C)= 77.2 ppm) as internal standard, and coupling constants (J) are given in Hz.…”

“…1 H NMR (400 MHz, CDCl3) δ: 10.99 (s, 1H), 8.88 (dt,J = 5.2,3.8 Hz,2H),8.18 (dd,J = 8.3,1.7 Hz,1H),2H), 7.75 (dd, J = 8.4, 0.9 Hz, 1H), 7.60 (dt, J = 7.9, 1.0 Hz, 1H), 7.58 -7.45 (m, 6H), 7.36 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ: 157. 3, 154.0, 148.6, 142.9, 138.9, 137.8, 136.5, 134.3, 132.1, 130.3, 128.7, 128.2, 127.9, 127.5, 125.9, 124.1, 122.2, 121.9, 121.8, 117.2, 112.4, 94.8.…”

“…In our group, we saw an interesting opportunity to access a diverse set of structurally elaborate benzofuran-2-carboxamide derivatives that carries different substituents in the C3 position through a strategic use of 8-aminoquinoline (8-AQ) directed C-H functionalization chemistry followed by a two-step transamidation method of 8-AQ amides developed within our group (Scheme 1c). [12] 8-AQ directed C-H functionalizations have is the recent decade become very popular within the fields of drug discovery [13] and natural product synthesis, [14] since they often enable for rapid assembly of molecular complexity.…”

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives through a Combination of 8-Aminoquinoline Directed C–H Arylation and Transamidation Chemistry

“…In our group, we identified an interesting opportunity to access a diverse set of benzofuran-2-carboxamide derivatives housing different substituents in the C3 position, by combining 8-aminoquinoline (8-AQ) directed C-H functionalization chemistry with a two-step transamidation protocol for 8-AQ amides that had been previously developed within our lab (Scheme 1c) [59]. Since 8-AQ directed C-H functionalization chemistry [60][61][62] allows for rapid assembly of molecular complexity, it has found extensive use within the fields of drug discovery [63][64][65][66][67][68][69][70] and natural product synthesis [71][72][73][74][75][76][77]. Inspired by this prior art, we sought to leverage this powerful methodology when designing a modular and robust synthetic route towards our target benzofuran-2-carboxamide derivatives.…”