Organosilanols

Powerful Nucleophiles for Cross-Coupling

Over the past several years, the Pd-catalyzed cross-coupling of silicon compounds (Hiyama coupling) has rapidly gained acceptance as a suitable alternative to more commonly used methods such as Stille (Sn), Kumada (Mg), Suzuki (B), and Negishi cross-couplings (Zn).¹ In particular, considerable progress has been made in the cross-coupling reactions of organosilanols and organosilanolates. Advantages of these organometallic nucleophiles include:

1. Low toxicity
2. Ease of preparation from inexpensive starting materials⁵
   1. Metal-halogen exchange or directed metallation
   2. Transition metal-catalyzed silylation of aryl halides
   3. Hydrosilylation
3. Certain stoichiometry
4. Robustness with respect to air and moisture stability
5. Cross-coupling substrate scope
6. Ability to cross-couple under fluoride or basic (via silanolate) activation

Alkenyl(dimethyl)silanol coupling: Preparation of diene and styrene derivatives

Using a fluoride activator, alkenyl(dimethyl)silanols readily couple with both aryl and alkenyl halides to give the coupled adducts in very good yield (Scheme 1).⁵ Alternatively, the Pd-catalyzed cross-coupling can be performed under basic activation using TMSOK for in situ generation of a nucleophilic silanolate.^7-8 The utility of this performing the cross-coupling under basic activation, lies in the ability to couple in the presence of fluoride-sensitive silyl protecting groups as illustrated in Scheme 2.⁹ Alkynylsilanols have also been found to be active coupling partners under similar conditions.¹⁰

Both strategies, fluoride and base activation, were demonstrated in the total synthesis of the antifungal polyene macrolide RK-397.¹¹ Specifically, the polyene segment of the natural product was prepared by sequential cross-coupling of a differentiable 1,4-bissilylbutadiene unit (Scheme 3). The dimethylsilanol moiety readily couples under basic activation (via a silanolate), while the other silyl substituent remains inert. Subsequent fluoride-promoted coupling of the benzyldimethylsilyl group provided the necessary tetraenoate linkage for completion of the target molecule.

Aryl(dimethyl)silanol coupling: Preparation of biaryls (and heterobiaryls)

Robust experimental protocols have been developed for biaryl coupling of aryl- and heteroaryl-(dimethyl)silanols with a variety of aryl iodides and bromides.^13-14 Excellent yields were obtained in the coupling of (4-methoxyphenyl)dimethylsilanol with a diverse set of aryl halides using Cs₂CO₃ to generate the silanloate in situ (Scheme 4). Aryl bromides could be coupled using dppb as a ligand additive in toluene, while coupling of iodides was most effective using Ph₃As in dioxane.

Entry	R	X	Time (h)	Additive	Solvent	Yield (%)
1	4-CO2Et	Br	24	dppb	toluene	90
2	4-CH3	Br	18	dppb	toluene	90
3	4-H	Br	12	dppb	toluene	85
4	4-OCH3	Br	18	dppb	toluene	92
6	2-CH3	I	24	PhaAs	dioxane	85
7	2-CF3	I	24	PhaAs	dioxane	82
8	2-NO2	I	24	PhaAs	dioxane	83
9	4-Ac	I	3	PhaAs	toluene	91

Until recently, mild and general methods for cross-coupling of 2-heteroaryl organometallic nucleophiles were lacking. Boc-protected indoles are particularly challenging coupling substrates, owing to the decreased nucleophilicity at C-2. Typical procedures called for harsh reaction conditions (Stille coupling¹⁵) or failed to deliver the coupled product in acceptable yield (Suzuki coupling^16-17). Denmark and co-workers have developed a set of general protocols for efficient coupling of these difficult substrates (Scheme 5). Both protocols call for generation of a sodium silanolate (basic activation). Silanolates generated in situ from NaOt-Bu undergo Pd-catalyzed cross-coupling with aryl iodides in the presence of CuI. Alternatively, silanolates generated in situ from NaH can be coupled without an additive.⁶ Finally, sodium dimethylsilanolates are also isolable and storable materials whose reactivity parallels that of in situ-formed silanolates.

Entry	R	Base	Additive	Temp (o C)	Time (h)	Yield (%)
1	4-NO2	NaOt -Bu	Cul	rt	6	84
2	4-CF3	NaOt -Bu	Cul	rt	22	82
3	2-OCH3	NaOt-Bu	Cul	50	24	75
4	4-OCH3	NaOt-Bu	Cul	50	24	72
5	4-CN	NaH	None	rt	3	81
6	4-CO2Et	NaH	None	rt	3	82
7	4-OCH3	NaH	None	80	3	68

This methodology is applicable to cross-coupling of other heteroaryl(dimethyl)silanols with aryl iodides in the presence of Pd₂(dba)₃•CHCl₃.^6,19 Thiophene, furan, and pyrrole nucleophiles easily couple with both electron-rich and electron-deficient aryl iodides (Scheme 6).

Less expensive aryl bromides can be used in the reaction by changing to a highly-active Pd(I) catalyst developed by the Weissman and Moore groups (Scheme 7).¹⁹ The reactions times are generally shorter than with aryl iodides with no discernable decrease in yields. The Pd(I) catalyst displays very high activity that is comparable to or superior than many commonly used cross-coupling catalysts. It is readily prepared from (2-methylallyl)palladium(II) chloride dimer and P(t-Bu)₃ in the presence of base.

1. 2002. Design and Implementation of New, Silicon-Based, Cross-Coupling Reactions:  Importance of Silicon?Oxygen Bonds. Acc. Chem. Res.. 35(10):835-846. https://doi.org/10.1021/ar020001r

2. Denmark SE, Sweis RF. 2002. Cross-Coupling Reactions of Organosilicon Compounds: New Concepts and Recent Advances. 50(12):1531-1541. https://doi.org/10.1248/cpb.50.1531

3. Denmark SE, Ober MH. Organosilicon reagents: Synthesis and application to palladium-catalyzed cross-coupling reactions. Aldrichimica Acta. 36(3):75-85..

4. Denmark SE, Wehrli D. 2000. Highly Stereospecific, Palladium-Catalyzed Cross-Coupling of Alkenylsilanols. Org. Lett.. 2(4):565-568. https://doi.org/10.1021/ol005565e

5. Denmark SE, Neuville L. 2000. Mild and General Cross-Coupling of (?-Alkoxyvinyl)silanols and -silyl Hydrides. Org. Lett.. 2(20):3221-3224. https://doi.org/10.1021/ol0064112

6. Denmark SE, Baird JD. 2006. Palladium-Catalyzed Cross-Coupling Reactions of Heterocyclic Silanolates with Substituted Aryl Iodides and Bromides. Org. Lett.. 8(4):793-795. https://doi.org/10.1021/ol053165r

7. Denmark SE, Sweis RF, Wehrli D. 2004. Fluoride-Promoted Cross-Coupling Reactions of Alkenylsilanols. Elucidation of the Mechanism through Spectroscopic and Kinetic Analysis. J. Am. Chem. Soc.. 126(15):4865-4875. https://doi.org/10.1021/ja037234d

8. Denmark SE, Sweis RF. 2004. Cross-Coupling Reactions of Alkenylsilanolates. Investigation of the Mechanism and Identification of Key Intermediates through Kinetic Analysis. J. Am. Chem. Soc.. 126(15):4876-4882. https://doi.org/10.1021/ja0372356

9. Denmark SE, Sweis RF. 2001. Fluoride-Free Cross-Coupling of Organosilanols. J. Am. Chem. Soc.. 123(26):6439-6440. https://doi.org/10.1021/ja016021q

10. Denmark SE, Tymonko SA. 2003. Cross-Coupling of Alkynylsilanols with Aryl Halides Promoted by Potassium Trimethylsilanolate. J. Org. Chem.. 68(23):9151-9154. https://doi.org/10.1021/jo0351771

11. Denmark SE, Fujimori S. 2005. Total Synthesis of RK-397. J. Am. Chem. Soc.. 127(25):8971-8973. https://doi.org/10.1021/ja052226d

12. Denmark SE, Tymonko SA. 2005. Sequential Cross-Coupling of 1,4-Bissilylbutadienes:  Synthesis of Unsymmetrical 1,4-Disubstituted 1,3-Butadienes. J. Am. Chem. Soc.. 127(22):8004-8005. https://doi.org/10.1021/ja0518373

13. Denmark SE, Ober MH. 2003. Cross-Coupling Reactions of Arylsilanols with Substituted Aryl Halides. Org. Lett.. 5(8):1357-1360. https://doi.org/10.1021/ol034328j

14. Denmark S, Ober M. 2004. Palladium-Catalyzed Cross-Coupling Reactions of Substituted Aryl(dimethyl)silanols. Adv. Synth. Catal.. 346(13-15):1703-1714. https://doi.org/10.1002/adsc.200404204

15. Labadie SS, Teng E. 1994. Indol-2-yltributylstannane: A Versatile Reagent for 2-Substituted Indoles. J. Org. Chem.. 59(15):4250-4254. https://doi.org/10.1021/jo00094a042

16. Tyrrell E, Brookes P. 2003. The Synthesis and Applications of Heterocyclic Boronic Acids. Synthesis. 2003(04):0469-0483. https://doi.org/10.1055/s-2003-37721

17. Johnson CN, Stemp G, Anand N, Stephen SC, Gallagher T. 1998. Palladium(0)-Catalysed Arylations using Pyrrole and Indole 2-Boronic Acids. Synlett. 1998(9):1025-1027. https://doi.org/10.1055/s-1998-1834

18. Denmark SE, Baird JD. 2004. Palladium-Catalyzed Cross-Coupling Reactions of 2-Indolyldimethylsilanols with Substituted Aryl Halides. Org. Lett.. 6(20):3649-3652. https://doi.org/10.1021/ol048328a

19. Denmark SE, Bui T. 2005. Mechanistic Insights into the Chiral Phosphoramide-Catalyzed, Enantioselective Crossed-Aldol Reactions of Aldehydes. J. Org. Chem.. 70(25):10393-10399. https://doi.org/10.1021/jo051680x