Synthesis and application of solid alkyne-based zinc reagents stabilized by water-oxygenation

Synthesis and application of solid alkyne-based zinc reagents stabilized by water-oxygenation
Double-substituted alkynes have a wide range of applications in materials science and medicinal chemistry, and are also important precursors for the synthesis of olefins containing multifunctional groups, and the reaction of alkyne-based metal reagents with different electrophilic reagents is one of the main methods to obtain multisubstituted alkynes. Currently, several papers have reported the preparation of organometallic reagents stabilized against hydroxide by aromatic (hetero)cyclic, allyl and benzyl halides, among which organozinc reagents are promising for high-throughput screening of biologically active molecules, and solid-phase Reformatsky allyl alcoholization reactions have been able to be well applied in organic reactions. In addition, aromatic (hetero)cyclic zinc reagents are widely used in Co-catalyzed coupling reactions due to their availability in air. Recently, the group of Prof. Paul Knochel from the University of Munich, Germany, reported the synthesis of a new class of water-oxygen-stabilized alkyne-based zinc reagents, from which they successfully synthesized bisubstituted alkynes.

The authors synthesized alkyne-based zinc reagents (1) via terminal alkyne with TMPZnCl-Mg(OPiv)2 (3, TMP = 2,2,6,6-tetramethylpiperidine) with excellent compatibility for a wide range of functional groups. Initial studies showed that the reaction of trimethylsilylacetylene (2a) with TMPZnOPiv-LiCl gave the alkyne-based zinc reagent 1a, but it was poorly stabilized (retaining only 44% of its activity after 4 h in air), and they conjectured that the presence of LiCl might have contributed to the poor stability of the zinc reagent. They then used benzyl Grignard reagent to react with TMPH in THF, followed by the addition of Zn(OPiv)2, which allowed them to quantitatively obtain TMPZnOPiv (3), and the reaction of 3 with 2a gave the alkyne-based zinc reagent 1a, and still gave 90% yield after 4 h in air (Fig. 1). This approach allowed the authors to prepare alkyne-based zinc reagents containing functional groups such as carbonyl, cyano, and ester groups, which remained 43-90% reactive after 4 h in air.
Synthesis of alkyne-based zinc reagents. Image credit: Angew. Chem. Int. Ed.
Next, they applied the prepared alkyne-based zinc reagents to the Negishi coupling reaction (Figure 2). Through the screening of conditions, the authors finally determined that Pd(dba)2 binds to DavePhos ligand with the best catalytic activity, under which a series of aromatic (hetero)cyclic iodo-substituents, bromo-substituents, and chloro-substituents were able to react with the alkynyl zinc reagents to obtain the target products; moreover, ester, acyl, methoxy, cyano, secondary amine, and amide moieties were all found to be well-compatible, and the aromatic In addition, the compatibility of ester group, acyl group, methoxy group, cyano group, secondary amine group, amide group, etc., and the participation of aromatic heterocyclic modified alkynyl zinc reagent in the reaction also gave the desired yield.

Negishi coupling of alkynyl zinc reagent 1. Image credit: Angew. Chem. Int. Ed.
This class of alkyne-based zinc reagents can also be involved in other transition metal-catalyzed coupling reactions (Figure 3). Alkynyl zinc reagents 1e with thiocarboxylates 7 can give alkynyl ketones 8 catalyzed by Pd; 1j with allyl bromides 9 via CuCN-2LiCl catalyzed to give allyl alkynes 10; and 1c can be used to give propargyl alcohols by nucleophilic addition to aldehydes.
Other coupling reactions of alkyne zinc reagents. Image credit: Angew. Chem. Int. Ed.
In addition to this, they found that alkyne-based zinc reagents can also undergo a Cu-catalyzed Click reaction (CuAAC) to regioselectively give 1,4-disubstituted triazoles (Figure 4). Alkynyl zinc reagents 1 can be coupled with aryl azides or in situ generated benzyl azides (prepared by the reaction of benzyl bromide with NaN3) to give CuI-catalyzed zinc reagents of triazoles, which are coupled with electrophilic reagents to give polysubstituted 1,2,3-triazoles (6a-d).

Cu-catalyzed 1,3-dipolar cycloaddition reaction. Image credit: Angew. Chem. Int. Ed.
On this basis, they also applied this reaction to the synthesis of 18, a drug with potential antitumor activity, where compound 22 was reacted in situ with NaN3 to give a benzyl azide, which was coupled with the alkyne zinc reagent 1d to give the key triazole intermediate 23, which was subsequently reacted to give the final product 18
Synthesis of carboxamide triazole 18. Image credit: Angew. Chem. Int. Ed.
Prof. Paul Knochel’s group reports a new method for the synthesis of alkyne-based zinc reagents, which have good stability to aqueous oxygen as well as functional group compatibility and can be applied in coupling reactions with a wide range of aryl, alkyl and acyl groups. This class of zinc reagents can also undergo Cu-catalyzed