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Catalytic Generation of Silicon Nucleophiles

Koji Kubota and Hajime Ito

Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Hokkaido, 060-8628, Japan

Faculty of Engineering, Division of Applied Chemistry and Frontier Chemistry Center, Hokkaido University, Kita 13 Nishi 8, Kita-ku, Sapporo, Hokkaido, 060-8628, Japan

1.1 Introduction

Silicon nucleophiles represent a class of important organometallic species for silicon-carbon, silicon-silicon, and silicon-boron bond formation reactions in synthetic chemistry [1]. Conventionally, the generation of silicon nucleophiles is accomplished by reactions of chlorosilanes with alkali metal (K, Na, Li), reactions of hydrosilanes with alkali metal hydride, cleavage of the silicon-silicon bond in disilanes or the silicon-boron bond in silylboron reagents by organometallic carbon nucleophiles, and transmetallation from other silicon-metal compounds [2]. However, these stoichiometric methods have significant limitations such as low functional-group compatibility due to the high reactivity of hard silyl anions with an alkali metal countercation. In this context, silicon-based organocuprates are widely used as soft silyl anion equivalents for silicon-carbon bond formation reactions, even though this method requires stoichiometric organometallic compounds and copper salt [3]. Recently, catalytic nucleophilic silylation reactions have attracted considerable attention because of their mild reaction conditions and unique selectivity and reactivity. This chapter mainly focuses on two types of activation modes for catalytic generation of silicon nucleophiles (Figure 1.1). First, transmetalation between silicon compounds containing a Si─X bond (X = Si, B, and Zn) and metal catalysts generates nucleophilic silyl metal intermediates (Figure 1.1a). Second, a catalytic amount of Lewis bases (Nu) activates the silicon-boron bond of silylboron reagents to form nucleophilic silyl species (Figure 1.1b). This chapter provides the recent advancements in the catalytic generation of silicon nucleophiles through these activation pathways and their applications in organic synthesis.

Figure 1.1 Representative pathways for catalytic generation of silicon nucleophiles. (a) Metal-catalyzed method. (b) Lewis base-catalyzed method.

1.2 Silicon Nucleophiles with Copper Catalysts

1.2.1 Copper-Catalyzed Nucleophilic Silylation with Disilanes

1.2.1.1 Silylation of a,ß-Unsaturated Carbonyl Compounds

In 1998, the first example of copper-catalyzed nucleophilic 1,4-silylation of a,ß-unsaturated carbonyl compounds with disilanes was reported by Ito et al. (Scheme 1.1) [4]. The reaction of cyclohexanone with a disilane in the presence of a copper salt and Bu3P as a ligand proceeded to give the corresponding 1,4-silyl addition product in high yield. The silylation presumably goes through the s-bond metathesis between a copper salt and a disilane to form the silylcopper intermediate, followed by its 1,4-addition to cyclohexanone. The copper catalyst is regenerated by the reaction between the resultant copper enolate and silyl triflate, which is formed at the first stage of this cycle. This mild protocol can be applied to a variety of substrates such as a,ß-unsaturated cyclic and linear ketones and aldehydes to form the ß-silyl carbonyl compounds in high yields.

Scheme 1.1 Copper-catalyzed silylation of a,ß-unsaturated carbonyl compounds with a disilane.

1.2.1.2 Silylation of Alkylidene Malonates

Scheidt and coworkers reported the copper-catalyzed nucleophilic silylation of alkylidene malonates with disilanes in 2004 (Scheme 1.2) [5]. They found pyridine to be an effective ligand rather than phosphines for this reaction.

Scheme 1.2 Copper-catalyzed silylation of alkylidene malonates with a disilane.

1.2.1.3 Silylation of Allylic Carbamates

In 2012, Ito et al. developed the copper-catalyzed allylic substitution with silicon nucleophiles (Scheme 1.3) [6]. This is the first example of a copper-catalyzed reaction between a disilane and allylic carbonates to produce allylsilanes, which are particularly useful reagents for stereoselective allylation of aldehydes in the presence of Lewis acids [7]. The regioselectivity of this reaction depends on the structure of substrates, suggesting that this reaction would proceed through the formation of a p-allyl copper(III) intermediate.

Scheme 1.3 Copper-catalyzed silylation of allylic carbamates with a disilane.

1.2.2 Copper-Catalyzed Nucleophilic Silylation with Silylboronate

1.2.2.1 Silicon-Boron Bond Activation with Copper Alkoxide

Although disilanes are powerful sources for the generation of silicon nucleophiles as described, recent attention has focused on exploring the unique reactivity of silylboronates [8]. The difference in Lewis acidity between silicon and boron of silylboronates is exploited for facile boron-metal exchange at the silicon atom to generate silicon nucleophiles. The silicon-boron bond activation by s-bond metathesis with copper alkoxide catalysts has become a general technique to access copper-stabilized silicon nucleophiles due to its mild reaction conditions (Figure 1.2) [8].

Figure 1.2 Activation of silicon-boron bond by s-bond metathesis with a copper alkoxide.

1.2.2.2 Silylation of a,ß-Unsaturated Carbonyl Compounds

In 2010, the first example of copper-catalyzed nucleophilic silylation of a,ß-unsaturated carbonyl compounds with silylboronates was reported by Hoveyda and a coworker (Scheme 1.4) [9]. They found that the copper-based chiral N-heterocyclic carbene (NHC) complex, generated in situ from the reaction of the corresponding silver-based carbene precursor with CuCl and Na(O-t-Bu), efficiently catalyzed conjugate silyl addition to cyclohexenone to form chiral ß-silyl ketone in high yield with excellent enantioselectivity. Acyclic unsaturated ketones and cyclic dienones also undergo the enantioselective silyl conjugate addition with good to high enantioselectivity. Later, they also developed regio- and enantioselective conjugate silyl additions of acyclic and cyclic dienones and dienoates with a chiral NHC/copper complex catalyst [10].

Scheme 1.4 Copper-catalyzed enantioselective conjugate silyl addition with a silylboronate.

Soon after, Riant and coworkers reported the copper-catalyzed asymmetric silylative aldol reaction between a,ß-unsaturated carbonyl compounds and aromatic aldehydes (Scheme 1.5) [11]. The in situ-generated silylcopper intermediate reacts with methacryloxazolidinones to form the ß-silylcopper enolate, followed by a diastereoselective aldol reaction to give the products bearing a chiral quaternary carbon center with excellent stereoselectivity.

Scheme 1.5 Copper-catalyzed silylative aldol reaction with a silylboronate.

In 2011, Córdova and coworkers reported that a copper-catalyzed silylation method can be combined with a chiral amine cocatalyst for iminium activation, as exemplified by the catalytic enantioselective silyl addition to a,ß-unsaturated aldehydes (Scheme 1.6) [12].

Scheme 1.6 Enantioselective silylation of a,ß-unsaturated aldehydes by a copper/chiral amine cooperative catalyst.

The known copper-catalyzed silylation methods are generally sensitive to moisture and need to be carried out under an inert atmosphere. However, in 2012, Santos and a coworker discovered that the conjugative silylation of carbonyl compounds in water under air was efficiently catalyzed by a copper salt and 4-picoline (Scheme 1.7) [13]. Both copper and pyridine are required in this reaction. The role of the pyridine is proposed to deprotonate a nucleophilic water molecule to form an sp3-hybridized silylboronate, followed by transmetalation with copper to generate a silylcopper active species.

Scheme 1.7 Copper-catalyzed silylation of a,ß-unsaturated carbonyl compounds in water at room temperature.

The incorporation of silicon atoms into amino acids and peptides has attracted significant attention due to the large number of applications in chemical biology, and even as therapeutic agents [14]. The known methods for the preparation of silicon-containing amino acids have some limitations such as functional-group incompatibility due to the use of highly reactive carbon nucleophiles [15]. In 2015, Piersanti and coworkers developed the mild copper-based catalytic method for the regioselective silyl addition of dehydroalanine derivatives (Scheme...