An operationally simple approach to (E)-α-halo vinyl sulfides and their applications for accessing stereodefined trisubstituted alkenes

Abstract

An operationally simple and practical protocol for the synthesis of (E)-α-halo vinyl sulfides has been achieved via a highly regio- and stereoselective hydrohalogenation of alkynyl thioethers using lithium halides in HOAc or propionic acid at room temperature. It permits the formation of (E)-α-chloro and (E)-α-bromo vinyl sulfides in satisfactory yields with good to excellent stereoselectivities. Moreover, this work results in a new method for the assembly of stereodefined (E)- or (Z)-trisubstituted alkenes featuring the first coupling of the C-X bond of (E)-α-halo vinyl sulfides followed by a subsequent Ni-catalyzed coupling of the C-S bond with Grignard reagents.

Regio- and Stereoselective Synthesis of 1,2-Dihaloalkenes Using In-Situ-Generated ICl, IBr, BrCl, I2, and Br2

“…It should be noted that our protocol displayed much better regioselectivities compared with the reported method. 20 Our iodochlorination system could be extended to other diverse alkyne types such as highly electron-deficient sulfonyl alkynes (Figure 1, 50-57), 71 Despite the wide structural diversity of the above alkynes, our dihalogenation afforded products with exclusive or very high regioselectivity. We investigated the regioselectivity of internal alkynes that exhibited small structural biases (R 1 and R 2 ) on each end of the triple bond (Figure 1, 58-64).…”

Au-Catalyzed Intermolecular [2+2] Cycloadditions between Chloroalkynes and Unactivated Alkenes

“…Likewise, its reaction with phenylboronic acid was equally chemoselective and highly efficient, affording 7c in nearly quantitative yield. While the phenyl sulfide moiety was an innocent bystander in these Suzuki—Miyaura reactions, it can participate in Ni-catalyzed Kumada cross coupling with methyl Grignard 14 and hence offers a valuable site in the cyclobutene products for further functionalization/derivatization. For example, in a two-step sequence with 7c as the intermediate, the methylated 7d was formed in a combined 70% yield.…”

Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide Peptides

“…[31] Halide addition (LiBr (10 equiv,H OAc (1 equiv), rt, 18 h) using reportedc onditions that exclusively add to the a-position due to the electronic bias of the thioalkyneafforded the macrocycle 20 (53 %), where the bromide handle opens avenues to generate complexity via cross-coupling. [32] Azide-alkyne cycloadditions have already demonstrated significant potentialf or peptide modification and conjugation, [33] but these strategiesn ormally involved the popular Cu-catalyzed variant (CuAAC). An underexplored version involves Ir-catalyzed AAC on alkynyls ulfides which has been shown experimentally to exclusively form the 5-sulfenyl-1,2,3-triazole.…”

“…The resulting α,β‐unsaturated sulfone is an advantageous functionality for diversification via cycloaddition chemistry, [30] and possibilities for annulation to form heterocycles [31] . Halide addition (LiBr (10 equiv, HOAc (1 equiv), rt, 18 h) using reported conditions that exclusively add to the α‐position due to the electronic bias of the thioalkyne afforded the macrocycle 20 (53 %), where the bromide handle opens avenues to generate complexity via cross‐coupling [32] . Azide‐alkyne cycloadditions have already demonstrated significant potential for peptide modification and conjugation, [33] but these strategies normally involved the popular Cu‐catalyzed variant (CuAAC).…”