Technical Library

The study of various aryltrialkoxysilanes, principally trimethoxy and triethoxy derivatives, in cross-coupling applications indicates the wide potential for such systems in the synthesis of biaryls and styrene derivatives. A large number of examples are known a few of which are shown herein. Thus, the commercially available phenyltriethoxysilane can be coupled with aryl bromides to give the corresponding biaryl in good to excellent yields (Eq. 61).61 Sterically hindered aryl bromides couple well with the aryltriethoxysilanes (Eq. 62).62 Diphenyldimethoxysilane provides the phenyl group in the cross-coupling with aryl bromides (Eq. 63).61 Both phenyl groups can be incorporated.

Allyl benzoates react with aryl triethoxysilanes under cross-coupling conditions providing the allylbenzene derivative (Eqs. 66, 67).63,64

A similar reaction is possible with the Bayless-Hillman allyl acetates to form α-benzylated α,ß-unsaturated esters. (Eqs. 68, 69).65

ln addition to the standard trimethoxysilyl or triethoxysilyl reagents, the silatranes are also viable reagents for cross-coupling reactions (Eq. 70).66 Some silatranes show high levels of toxicity.

Vinyltrimethoxysilane and allyltrimethoxysilane, both commercially available, will react with aryl iodides under cross-coupling conditions to provide the corresponding styrene or allylbenzene derivative, respectively (Eqs. 71, 72).67

A fluoride-free, aqueous-based cross-coupling of aryl bromides and iodides with arylsilyl esters using an inexpensive Pd catalyst and a surfactant (SDS) provides a practical approach to silicon-based cross-couplings (Eq. 73).68 This very fast reaction is proposed to go through ‘in-situ’-generated palladium particles. Moreover, the reaction can be performed in air.

A 2-(2-dicyclohexylphosphino)phenylindol ligand (CM-Phos) and Pd(OAc)2 allows the coupling of arylsilyl esters with aryl mesylates. The reaction is promoted by small amounts of acetic acid (Eq. 74).69

The spiroarylphosphite, 2, with Pd(acac)2 and TBAF bring about the cross-coupling of phenyltrimethoxysilane with various aryl bromides (Eq. 75).70 Yields are modest to good.

The cross-coupling of arylsilyl esters with aromatic tosylates and related esters has been reported (Eq. 76).71 The XPhos ligand proved to provide the best yields. An aryl chloride reacts better than the corresponding tosylate (Eq. 77).

The cross-coupling of arylsilyl esters with aryl mesylates is carried out with TBAF and Pd(OAc)2 in excellent yields (Eq. 78).72 The ligand XPhos provides the better yields.

The combination of an imidazolium salt with palladium acetate cross-couples vinyl- and aryltrialkoxysilanes with aryl bromides and chlorides (Eqs. 79, 80, 81).73 Although the chlorides react more slowly they give comparable yields with the exception of electronic-rich systems.

The ligand, 1, was found to bring about the palladium-catalyzed cross-coupling of aryltrimethoxysilanes with aryl chlorides in good yields (Eq. 82).74

The direct cross-coupling of an arylsilyl ester with indoles provides a convenient route to 1-aryl indoles (Eq. 83).75

In an interesting approach to ortho-functional biaryl systems the silylation of acetophenone derivatives or the corresponding benzyl alcohol was used to prepare oxasiloles. The synthetic utility of the oxasiloles was demonstrated by a Tamao oxidation to the o-substituted phenols, and in the Hiyama cross-coupling for the formation of the o-functional biphenyl (Eq. 84).76

The direct ortho-arylation of acetanilides is possible with a variety of aryltriethoxysilanes. ln the case of a 3-substituted acetanilide the arylation occurs at the least hindered 6-position (Eq. 85).77

Silanols can be prepared in a number of ways; most commonly by way of careful hydrolysis of chloro-, amino-, or alkoxysilanes. The requisite aryl- or vinylsilane is oftentimes prepared by the reaction of a Grignard or organolithium reagent on the chloro- or alkoxysilane. The insertion of an ethoxydimethylsilyl group into an aryl iodide or bromide followed by hydrolysis of the ethoxy group to the silanol provides a direct route to aryldimethylsilanols without the need for and drawbacks of, a Grignard, or organolithium reaction to prepare the aryl silane (Eq. 86).78

ln a fashion similar to the cross-coupling of boronic acids with aryl and vinyl halides, aryl79 and vinylsilanols80 are useful in cross-coupling approaches to styrenes (Eqs. 87, 88) and conjugated dienes. These reactions are typically carried out in the presence of a base and are reactions of the in-situ-generated silanolate. ln the case of vinylsilanes, the reactions are stereospecific with respect to the geometry of the starting alkenylsilane (Eqs. 89, 90).79,81 The α-dimethylsilanol of an enol ether can be employed as well (Eq. 91).82

2-Arylindoles have been prepared in excellent yields by the cross-coupling of the 2-dimethylhydroxysilylindole with aryl bromides or iodides (Eq. 92).83

The reaction of vinylsilanols with aryltriflates or nonafluorosulfonates gives the corresponding styrene in good yields (Eq. 93).84

An example of the selective cross-coupling of a vinylsilanol in the presence of a 2-thienyldimethylsilyl group is known. This allows for the sequential cross-coupling of two sites on a molecule (Eq. 94).85

The readily prepared and easily handled disiloxanes under fluoride ion promotion undergo cross-coupling reactions (Eq. 95).86

An emphasis on the use of sodium or potassium silanolates in silicon-based cross-coupling reactions has surfaced recently. This has been in conjunction with and a result of thorough mechanistic studies that show that many of the protocols used in the cross-coupling of organosilanes proceed through a silanol or the corresponding silanolate. An excellent discussion of the history of the silicon-based cross-coupling reactions and the mechanism has been published.87 ln many ways this finding points the way to practical approaches using organosilanes as the nucleophilic partner in cross-coupling reactions as the silanolates are readily prepared and, though moisture sensitive, are otherwise very stable and easily handled. They also show good solubility in organic solvents and can be stored as solutions. The reactions do not require the use of fluoride promotion.

Bis(tert-butyl)phosphine palladium (0) is the key in the successful cross-coupling of aryl- and heteroarylsilanolates with aryl- and heteroaryl halides. A very thorough study of the range and applications of the methodology has been published (Eq. 96).88

An excellent review that looks into the history of the silicon-based cross-coupling methodology and the arrival at the true mechanisms of the reactions has been published. The importance of silanols and silanolates in these important transformations is well documented therein (Eq. 97).87

Based on a thorough study of the mechanism of the silicon-based cross-coupling reaction it was discovered that phosphine oxides, such as triphenylphosphine oxide, are excellent and inexpensive ligands for the transformations. The combination of allylpalladium chloride dimer (APC) and triphenylphosphine oxide proves to be an excellent one for the cross-coupling of potassium silanolates with aryl bromides (Eq. 98).89

The reaction of heterocyclic sodium silanolates, generated ‘in-situ’, with aryl iodides and bromides gives good yields of the biaryls (Eq. 99).90 A special Pd(I) catalyst, 5, is required for best results.

A major paper covering the use of potassium and sodium silanolates in the cross-coupling of arylsilanes with aryl and vinyl halides has appeared (Eqs. 100, 101).88 This work demonstrates the practicality and strong potential for the use of arylsilanolates in silicon-based cross-coupling protocols. Good yields obtained with both electron-poor and electron-rich as well as sterically-hindered electrophilic partners. The key to the success of these cross-coupling reactions is the use of (t-Bu3P)2Pd (0) catalyst of choice. No other special ligands or fluoride are required.

A combination of Larock heteroannulation and silicon-based cross-coupling leads to 2,3-disubstituted indoles (Eq. 102).91 Silanols as well as silanolates can be the nucleophilic reagents employed in the cross-coupling. The silyl group employed both to direct the regioselectivity of the heteroannulation and bring about the cross-coupling.

Advances in the technology applied to the silicon-based cross-coupling reactions have led to the employment of special ligands attached to silicon through Si-C bonds. The purpose of this approach is to avoid the need for the fluoride ion promotion of the reactions and to add to the stability and ease of handling of the organosilanes. A key requirement of the special ligand approach is that the activating ligand on the silicon atom is not involved in the cross-coupling itself. Among such useful systems employed are the 2-thiophenylsilanes 6, the 2-pyridylsilanes 7, benzyldimethylsilanes, 8, and the o-hydroxymethylphenylsilanes 9. These ligands activate the silane for the cross-coupling reaction without themselves being transferred.

The 2-thiophenylsilane derivatives 6 have been employed in the tag strategy for the separation, recovery and recycling of the precursor to the reactive intermediates themselves. Many of these reagents still require the promotional effect of fluoride ion in their reactions (Eqs. 103, 104).92

Advantage was taken of the 2-thienyl ligand, Th, on silicon to prepare stereodefined (E) and (Z)-poly(p- phenylenevinylene)s via the hydrosilylation of p-diethynylbenzene with 2-thienyldimethylsilane and then cross-coupling with diiobenzene derivatives (Eqs. 105, 106, 107, 108).93

The combined use of the 2-thienyl ligand in the silicon-based cross-coupling and of the silyl group to dictate the regioselectivity of the intramolecular allylic alkylation prior to the cross-coupling step was employed in the synthesis of model systems for podophyllotoxin and picropodophyllin natural products (Eqs. 109, 110, 111).94

A second approach has been to employ the 2-pyridylsilane derivatives. Thus, vinyl(2-pyridyl)dimethylsilane, a thermally and hydrolytically stable system, undergoes a Heck coupling with aryl iodides (Eq. 112).95 With substituted vinylsilanes of this type the stereochemistry of the olefin is maintained (Eq. 113).95 The resulting vinylsilanes can then be further converted; for example, reaction with bromine gives the vinyl bromide (Eq. 114) and acylation provides the enone (Eq. 115).95

A one-pot, double-Heck coupling is possible as shown in Eq. 116.96 The sequential approach gives higher overall yields, however. The high reactivity of the 2-pyridylvinylsilane 12 towards the Heck reaction is illustrated in the competitive reaction experiment, wherein the selectivity for the Heck reaction of 12 with iodobenzene over that between iodobenzene and methyl acrylate or between iodobenzene and styrene is clearly shown (Eq. 117).96

A combination of a Heck reaction followed by a silicon-based cross-coupling reaction can be used to stereoselectively prepare (E)-1,2-diarylethylenes (Eq. 118).96,97 A one-pot version of this sequence is also possible (Eq. 119).97

The double-Heck-Hiyama cross-coupling sequence provides 1,2,3-triaryl ethylenes with the opportunity to introduce three different aryl groups (Eq. 120).96 Furthermore, the protodesilylation of the resulting vinylsilanes from the double Heck sequence leads to 1,1-diarylethylenes. (Eq. 121).96

The presence of the 2-pyridyl ligand on alkenyldimethylsilanes allows for the cross-coupling of the alkenyl group with aryl iodides (Eq. 123) The 2-pyridyl group is a precursor to the reactive silanol (Eq. 122).98

The (2-hydroxymethylphenyl)silane-derived silacycle 15 can be reacted with aryl or vinyl Grignard reagents or their organolithium counterparts to give the corresponding vinyl(2-hydroxymethylphenyl)silane or the aryl(2-hydroxymethylphenyl)silane, for example 13 or 14 (Eq. 124). The o-hydroxymethyl group provides an activating effect for the effective cross-coupling of the aryl group with aryl or vinyl halides (Eq. 125).99 A potentially significant aspect of this approach is that the silabenzofuran is regenerated during the cross-coupling reaction and can be recycled.

This recycling aspect was put to use illustrating where the silabenzofuran can be employed for the essential cross-coupling of aryllithiums to aryl halides. Thus, the silabenzofuran operates as a carrier for the organolithium reagent allowing its reaction with an aryl halide, a reaction the aryllithium reagent itself is not capable of in good yield (Eq. 126).100

The hydrosilylation of terminal acetylenes under Karstedt catalysis, (bis-divinyltetramethyldisiloxanyl platinum(0)) gives the (E)-vinylsilane carrying the o-hydroxymethylphenyl promoter group. Cross-coupling of the (E)- vinylsilane with aryl iodides gives 2-aryl olefins in excellent yields (Eqs. 127, 128).101,102

The arylated systems with the o-hydroxymethylphenyl promotion also couple with allyl and benzyl carbonates (Eqs. 129, 130).103 Related chemistry presents advantages for the cross-coupling with electron-poor electrophilic partners.

Taking advantage of the strong reactivity of the (2-hydroxymethylphenyl)dimethylarylsilanes and the non-reactivity of the OH-protected (THP or Ac) derivative it has proven possible to iteratively construct oligomeric systems in good yields and with specificity (Eq. 131).104 The iterative synthesis of polythiophenes is an excellent example of this activation-deactivation approach.

Hiyama and coworkers have employed the (2-hydroxymethyl)phenylsilane system to transfer an alkyl group from silicon to aryl halides, including aryl chlorides. They have used a 2-hydroxypropyl system, leading to the gem-dimethylbenzosilafuran by-product, to significant advantage in these reactions (Eq. 132).105 No reaction of the phenyl-Si bond is seen under these conditions. With the simple hydroxymethyl analog only the benzaldehyde and reduction of the aryl chloride are observed.

ln work that mimics that of the 2-hydroxymethylphenylsilane cross-couplings the specialty ligand prepared from cis-2-(2-hydroxypropyl)cyclohexyldimethylarylsilanes can be used in nickel-catalyzed cross-coupling reactions with aryl chlorides and tosylates (Eq. 133).106 Recycling of the parent silicon reagent is again possible.

Another example of intramolecular activation of an arylsilane for cross-coupling is shown in the example of 8-tert– butyldimethylsilyl-1-naphthols, prepared via a Diels-Alder approach, and their cross-coupling with aryl iodides (Eq. 134).107