The ability of available organosilanes to both silylate alcohols and hydrosilylate alkynes can be used to generate interesting stereo-defined, organofunctionalized olefins. For example, the O-silylation of a hydroxyalkyl acetylene with sym-tetramethyldisilazane followed by intramolecular hydrosilylation of the acetylene provides an intermediate vinylsilane, which also has the requisite alkoxy substituent for cross-coupling. The stereochemical outcome of the reaction is determined by the cis hydrosilylation resulting from the intramolecular hydrosilylation step (Eqs. 135, 136).108,109 Tetramethyldisiloxane is useful in this type of templated cross-coupling approach as well (Eq. 137).110
The use of 2-(1,3-butadienyl)silatrane in a Diels-Alder-cross-coupling sequence provides an entry into 1-arylated cyclohexenes (Eq. 138).111
An O-silylation, cross-metathesis, cross-coupling sequence can be employed in the generation of interesting species via inter- or intramolecular processes (Eqs. 139, 140).112-115 This general approach was used in a synthesis of (17Z) oximidine I, 17, and (17E) oximidine III, 18.116
Starting with a silylalkyne the silyl group can be used to direct the regioselective cycloaddition with an in-situ-generated nitrile oxide to generate the 4-silylisoxazole (Eq. 141).117 The regioselectivity is only about 4:1, but any undesired 5-silyl isomer is hydrolyzed under acid conditions leaving only the desired isomer. This heteroarylsilane can then be cross- coupled with an aryl iodide to prepare the 4-arylisoxazole (Eq. 142).117
A highly regio- and stereoselective Heck coupling to vinylsilanols is accomplished with APC (Eq. 143).118 Placement of the aryl group is beta to the silicon atom and the silicon group can be removed with fluoride treatment.
Vinylsilanols are shown to undergo Heck coupling (Eq. 144).119,120
A stereospecific arylation of (E)-1,2-bis(trimethylsilyl)ethylene is possible producing (Z)-2-aryl-1-trimethylsilylethylenes (Eq. 145).121
C-H activation was employed in the direct silicon-based arylation of enamides with modest to good yields (Eq. 146).122 The reactions are catalyzed with Pd(OAc)2 and promoted with AgF.
Displacement of the cyano group on aryl- or alkenyl cyanides is possible via a Heck coupling with vinylsilanes and rhodium catalysis (Eq. 147).123 The vinyl silane can be used for further reactions.
A sequence of a Heck coupling to give 19 and a homocoupling provides an excellent entry into 1,4-diaryl-1,3-butadienes and 1,1,4,4-tetraaryl-1,3-butadienes. This was successfully employed in the preparation of various arylated 1,3-butadienes with interesting photophysical properties (Eqs. 148, 149).97
In a nice series of papers the cross-coupling of N,N-dimethylcarbamoyltrimethylsilane with vinyl halides, aryl halides, benzyl halides and imidoyl chlorides was demonstrated as shown below. The result is the facile introduction of the dimethylamido group via a C-C bond formation (Scheme l).124-127
The sodium salts of allyldimethylsilanol and related allylsilanes are readily coupled with a variety of aryl bromides in good yields (Eq. 150).128 A combination of allylpalladium chloride dimer (APC) and triphenylphosphine oxide is best for the sterically unencumbered substrates whereas for the more sterically challenged systems the benzylidene acetone ligand, 20, proved best. The mechanism has been studied (Eq. 151).129
Vinylalkoxysilanes undergo a Grignard-type coupling with aldehydes to form enones (Eq. 152).130 A change in the conditions with the utilization of the chiral ligand, DTBM-SEGPHOS, results in enantioselective addition to the carbonyl (Eq. 153).130 The yields and ee values are very good.
A highly enantioselective alkynylation catalyzed by the dicationic (S)-BlNAP-Pd complex with a variety of alkynylsilanes and trifluoropyruvate is described (Scheme 2).131 The catalytic reaction is applicable to highly enantioselective addition of polyyne to trifluoropyruvate to construct α-trifluoromethyl-substituted tertiary alcohols. A highly enantioselective alkynylation catalyzed by the dicationic (S)-BlNAP-Pd complex with a variety of alkynylsilanes and trifluoropyruvate is described. The catalytic reaction is applicable to highly enantioselective addition of the polyyne to trifluoropyruvate to construct α-trifluoromethyl-substituted tertiary alcohols trifluoromethyl group. The SiMe2Ph, SiMe2Bu-t, (low yield and ee) and Si(OEt)3 (poor results) groups were also investigated.
Phenyltrimethoxysilane reacts with aromatic aldehydes under the influence of TBAF to give benzophenones (Eq. 154)132 and under essentially the same conditions, but with the addition of a palladium catalyst, provides the corresponding methyl benzoate (Eq. 155).132
A number of Michael additions of aryl, vinyl, and ethynyl silanes to α,ß-unsaturated carbonyl systems have been reported. The coupling of organosilyl esters with enones to form ß-aryl ketones is possible when catalyzed by a palladium phosphinous acid complex in water. (Eq. 156).133
Catalytic 1,4-addition of arylsiloxanes to enones was carried out at 75 °C in the presence of a dicationic palladium(II) catalyst in aqueous 1,4-dioxane (Eq. 157).134 A nitrile-free complex generated in situ from Pd(dba)2 and Cu(BF4)2 in the presence of dppe or dppben was recognized to be the best catalyst to achieve high yields for the representative enones and enals. Some Heck coupling is seen here as well.
Use of triisopropylsilylethynylsilanols gives selective ethynylation with retention of the triisopropylsilyl moiety (Eq. 158).135 A segphos ligand is used to impart the enantioselectivity in prior work that was limited in that ß-aryl enones reacted very poorly resulting in higher yields of the 1,3-diyne formation. A way to circumvent this is via the use of ethynylsilanols (Eq. 159).135
Aryltrifluorosilanes were cross-coupled in an enantioselective, 1,4-addition manner to enones. Best yields were obtained with Ph3Bi and PhBF3K. Phenyltrifluorosilane gave good yields and good to excellent enantiomeric ratios. Zinc fluoride was a good promoter for the silane reactions (Eqs. 160, 161).136
The cross-coupling of aryl- and alkenyltrifluorosilanes with enones to form ß-aryl- or ß-alkenylketones has proven possible in an enantioselective manner when catalyzed by a chiral, non-C2-symmetric, copper-based NHC (N-heterocyclic carbene). The reaction is proposed to proceed via an alkenyl- or aryl copper NHC N-heterocyclic intermediate generated via an in-situ-generated alkenyl- or aryltetrafluorosilicate (Eq. 162).137 The reaction requires a 50% excess of the silyl reagent and 1.5 equivalents of TASF for activation. The yields of the reaction are good to excellent with enantiomeric ratios ranging from 47 to 97%. The approach complements that of the 1,4-reduction of unsaturated ß-substituted enones.
The complex formed from Pd(CH3CN)4(BF4)2 and (R,R)-MeDUPHOS is a highly enantioselective catalyst for the asymmetric conjugate addition of aryltriethylsiloxanes to a variety of unsaturated ketones, lactones, and lactams (Eq. 163).138 Yields are good and ee values are excellent.
Aryltrimethoxysilanes couple well with primary alkyl bromides. Several examples are reported (Eq. 164).139
α-Cyanoalkyltrimethylsilanes are coupled to aryl bromides to give the α-aryl nitrile (Eqs. 165, 166).140
Lithium bis(trimethylsilylamide) provides the amine group in a cross-coupling amination of aryl bromides to form primary anilines (Eq. 167).141
The cross-coupling of a silyl enol ether with aryl bromides results in the α-arylation of the carbonyl system. Thus, the reaction of the trimethylsilyl enol ether of a ketone with an aryl bromide under palladium catalysis provides the α-arylated ketone with the regioselectivity dictated by that of the silyl enol ether (Eq. 168).142
The palladium-catalyzed γ-arylation of the silyl ketene acetals of α,ß-unsaturated esters is reported (Eq. 169).143 The reaction works best with ZnCl2 activation and Pd(dba)2. TES enol ethers are better than trimethylsilyl enol ethers for this transformation. The aryl chlorides and iodides did not work as well as the bromides. Methyltrioctylammonium chloride also catalyzes the reaction, but at a slower rate.
lndium trichloride or indium tribromide will catalyze the alkyl chloride alkylation of silyl enolates of aldehydes, ketones, esters, amides, thioesters (Eq. 170).144 A three-component, single-pot alkylation/allylations or alkylation/alkynylations combinations are also possible with lnBr3 as the catalyst (Eqs. 171, 172)144. Alkylations occur with alkyl chlorides capable of forming a strong carbocations. The yields are excellent.
The formation of 1,4-dicarbonyl systems results from the formation of a C-C bond from a silyl bis-enol ether system (Eq. 173).145 The overall connection of two α-carbons is the net result of such a transformation.
Triethyltrifluoromethylsilane can be employed to introduce the trifluoromethyl group onto aromatic rings in good yields under favorable conditions (Eq. 174).146
The alkoxyarylation of olefins can be accomplished via the reaction of the olefin with an alcohol and an aryltrimethylsilane in the presence of Selectfluor® and a gold catalyst (Eq. 175).147 The use of the aryltrimethylsilane gives less homocoupling as compared with the results using an arylboronic acid. lntramolecular coupling works as well (Eqs. 176, 177). An extension of the intramolecular version of this transformation can also be done with Ph3AuCl under similar conditions.148
Under catalysis of the combination of Cu(OAc)2, [Rh(cod)Cl]2 and promotion with TBAF the direct hydroarylation of acetylenes with arylsilyl esters results in the formation of a new C-C bond (Eq. 178).149 The addition of the aryl and H groups is predominantly syn (cis). When carried out in the presence of D2O the addition of the aryl moiety and deuterium occurs across the triple bond. Unfortunately, only symmetrical acetylenes were investigated so that the question of regioselectivity has not been addressed.
The expanding applications of cross-coupling reactions in organic syntheses have placed these reactions in the sphere of providing short and efficient routes to starting materials for sophisticated syntheses. Moreover, they provide excellent protocols for the preparation of intermediates and final active pharmaceutical ingredients. Their applications have spread to the syntheses of complicated multiaryl systems of importance in several electronic fields. As illustrated with the examples presented in this brochure the organosilane approach is viable for a range of cross-coupling combinations.
Due in part to their earlier discovery as well as their excellent results, the metal components needed in the cross-coupling methodologies have been dominated by boron, zinc and tin systems. Based on the wide-ranging examples presented
in this brochure, the author feels that the advantages of ease of handling, templating potential, and non-toxicity of the organosilanes will serve to promote the organosilane approaches to the carbon-carbon bond formation via cross-coupling and as viable alternatives to these more-established systems.