9. Copper Hydride Chemistry

Reviews. Lipshutz, B. H. Synlett 2009, 509; Deutsch, C.; Lipshutz, B. H.; Krause, N. Chem. Rev. 2008, 108, 2916; Diez-Gonzalez, S.; Nolan, S. P. Acct. Chem. Res. 2008, 41, 349; Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. 2007, 46, 498; Riant, O.; Mostefaï, N.; Courmarcel, J. Synthesis 2004, 2943.

Although copper hydride enjoys a rich history dating back to the mid-1800s,[256] modern usage of CuH in synthesis is well recognized to have begun with “Stryker’s reagent” (SR) in 1988.[257] That the phosphine-stabilized hexamer, [(Ph3P)CuH]6,[258] can be used catalytically, in particular with inexpensive and environmentally unoffensive silanes, has shifted the spotlight insofar as development of new methodologies is concerned toward asymmetric uses of these net hydrosilylation reactions. The early recipe of Stryker, calling for catalytic amounts of CuCl together with NaO-t-Bu to generate CuO-t-Bu,[257] is still used frequently, especially since (extremely air-sensitive) CuO-t-Bu is no longer commercially available. Key C-H bond constructions that rely on (Ph3P)CuH can be found in many syntheses; as examples: (1) (±)-trans-kumausyne,[259] proceeding through enone 166; (2) intermediate 167 en route to (+)-pinnatoxin A,[260] and 168, of brevetoxin A,[261] among many others. Nonetheless, advances have been made of late such that the precursor Cu-O bond no longer need be formed in situ from these salts; that is,

Cu(OAc)2•H2O has been found to be an attractive replacement that streamlines the procedure to CuH (a reagent that is tolerant of water or alcohols).[262] Usually, the phosphine is present prior to the addition of the silane to ensure stability of the CuH through complexation (Eqn. 1-9). Considerable effort is also being made to evaluate N- heterocyclic carbene (NHC) ligands as a means of avoiding phosphines altogether

(Eqn. 1-9)

(vide infra).[263] A brief summary of several combinations that generate CuH is shown in Table 1-4. Polymethylhydrosiloxane (PMHS)[264] is often listed as a 29mer, and as a stoichiometric source of hydride can vary widely in content between vendors.

Table 1-4. Methods for generation of CuH

Material from Lancaster (Lancaster, CA; catalog #L14561) appears to give reproducible CuH chemistry, while PMHS from Acros Organics can lead to different (vastly inferior) results. PMHS is used as received from the vendor, although it should be handled and stored under argon in a multiply septumed bottle to maximize lifetime. Tetramethyldisiloxane (TMDS; Alfa catalog #12934) is another inexpensive silane that, on occasion, is a superior source of hydride (vide infra). Also available from Alfa Aesar (Ward Hill, MA) are Fleming’s silane (PhMe2SiH; catalog #A17901), phenylsilane (PhSiH3; catalog #L04558), and diethoxymethylsilane (DEMS; catalog #A10153) that are occasionally used.

With several sources of mild hydride available, the focus of current CuH chemistry continues to be on catalytic asymmetric processes.[278] Thus, both 1,2- and 1,4-additions of hydride to a variety of electrophilic centers have been developed, where the level of chiral induction derives from the innate bias of the ligand-metal complex. Such interactions, specifically regarding the electronic effect of the P-Cu-P bite angle, have been the subject of a recent theoretical DFT study.[279] Much of the success realized to date with asymmetrically ligated CuH has come from a relatively small subset of either biaryl or ferrocenyl bis-phosphines. Most notably, selected biaryls of the BIPHEP (169)[280] and SEGPHOS (170)[281] series deserve heightened attention not only for their remarkable discriminatory structural features but also because of the high TONs now possible as their CuH complexes. The same is true for certain chelators in the JOSIPHOS series.[282] The biaryl ligands illustrated in Figure 1-3, and the ferrocenyl derivatives shown in Figure 1-5, are also commercially available both in quantity and in enantiomerically pure form. They are stable solids that need be stored to the exclusion of air (e.g., in a glove box) in order to avoid phosphine oxidation. Dipyridyl analogs (e.g., 171), used in conjunction with CuF2 and PhSiH3 in toluene, also display good stability.[283] Indeed, their influence on asymmetric hydrosilylations of simple aryl ketones is such that these reactions can be carried out even under an oxidating environment (i.e., in air), as had been observed previously in 1,2-additions.[284] TONs with 171, likewise, are impressive and can be as high as 100,000:1 in substrate-to-ligand (S/L), with ee’s usually >87% (Eqn. 1-10). Two ligands in this bipyridyl series, the parent Ar = phenyl and the xylyl analog shown (171), are commercially available in both antipodal forms.

Figure 1-3. Representative biarylphosphine ligands used in CuH chemistry.

(Eqn. 1-10)

Both ligand 171 and its parent, (S)-P-Phos (Ar = Ph), as their complexes with in situ–generated CuH, have been studied in asymmetric hydrosilylations of halogen-containing aryl ketones.[285] That is, a variety of ketones bearing either chloride or bromide in the α-, β-, or γ-positions undergo 1,2-carbonyl reduction in toluene at –20 °C, using phenylsilane as the source of hydride. Enantiomeric excesses typically exceed 90%, as illustrated by the examples below.

Both BIPHEP 169 and SEGPHOS 170 form highly kinetically reactive CuH complexes. [(R)-(-)-DTBM-SEGPHOS]CuH (172) has excellent shelf life at room temperature when protected from air during handling and storage.[286] It is made from Cu(OAc)2•H2O and excess PMHS in toluene, where each milliliter of a preformed 0.001 M solution used per millimole of substrate translates into S/L = 1000:1.

Preparation of [(R)-DTBM-SEGPHOS] CuH in a Bottle (0.001 M)[286]

An oven-dried, poly-coated amber glass bottle equipped with a stir bar was purged under argon and brought into the glove box. Cu(OAc)2•H2O (10 mg, 0.05 mmol) and (R)-DTBM-SEGPHOS (59 mg, 0.05 mmol) were added followed by dry toluene (44 mL), and the reaction mixture was allowed to stir for 2 h at RT. PMHS (6 mL) was added dropwise, and the mixture was allowed to stir for 30 min. The amber bottle was then sealed using a standard (Aldrich) Sure/Seal, or Oxford Sure/Seal, storage valve-cap, and preferably stored at 4 °C.

Hydrosilylations by complexed CuH have been applied to several substrate types (Scheme 1-17). As illustrated by the following examples, the stereochemical outcomes from both 1,2-additions (to aryl ketones[287] and aryl imines[288]) and 1,4-conjugate additions (cyclic ketones,[269] β-aryl[289] and/or β-silyl enoates,[290] and unsaturated lactones)[273] can be controlled by these ligand-accelerated reactions. One of the key “tricks” to this chemistry is to take advantage of the tolerance of CuH complexes to alcohols and water.[273] In fact, several methods rely on the presence of a bulky alcohol (e.g., t-BuOH) to significantly enhance reaction rates. It takes relatively little added alcohol (volume-wise) to accelerate the hydrosilylation, usually on the order of 1–3 equivalents. The role of this additive is usually ascribed to the more rapid quenching of an intermediate copper alkoxide or enolate, which necessarily generates a copper alkoxide, an ideal precursor to rapid reformation of CuH in the presence of excess silane.[273] Thus, the rate increase is presumably due to bypassing a slower metathesis step between Cu-O and Si-H bonds that is otherwise essential in the catalytic cycle for regenerating CuH.

Scheme 1-17. Representative substrate types amenable to CuH-catalyzed hydrosilylations.

Early in these studies with DTBM-SEGPHOS-ligated CuH, 172, the source of catalytic copper hydride (out of convenience) was Stryker’s reagent itself [i.e., the hexamer of (Ph3P)CuH].[257] In cases run at ambient temperatures, the “background” (and hence, competing) achiral addition of (Ph3P)CuH led to lower product ee’s. Thus, catalytic asymmetric hydrosilylations by CuH at room temperature should best be run using either [CuCl + NaO-t-Bu]- or [Cu(OAc)2•H2O]-based recipes. At temperatures of 0 °C or lower, ee’s are not likely to suffer from Ph3P present in solution. Nevertheless, Stryker’s reagent has a limited shelf life. Even a fresh bottle of reagent should be checked by 1H NMR for hydride (δ 3.50, in C6D6).[270, 291]

All of the examples shown (Scheme 6-17), except for aryl imines, have S/L ratios of >1000:1 (imines: ≤100:1). For selected educts such as acetophenone, the TON is >100,000 using either CuH complexed by ligand 169 or 170,[286] while for isophorone, it is ≥275,000:1 with (DTBM-SEGPHOS)CuH (procedure below).[269] 1,2-Additions are temperature sensitive in that ee’s improve as reactions are cooled toward –78 °C.[287] The variation in ee’s between temperatures can easily be >10%, and this is a limitation for larger scale applications. Moreover, at lower temperatures, there may be substrate solubility issues. Solvents other than toluene can be used...