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Suzuki-Miyaura Coupling and a-Arylation

Aldrich ChemFiles 2007, 7.5, 11.

Suzuki-Miyaura coupling reactions using a Pd catalyst derived from Q-Phos are highly successful for both electron-poor and electron-rich aryl bromides and chlorides (Table 3).1 As expected, aryl bromides are more reactive, and typically Suzuki couplings with arylboronic acids proceed at ambient temperature (entry 3). While reactions of aryl chlorides with aryl boronic acids typically require heating for extended periods, yields are generally quite high (.90%). Additionally, alkylboronic acids couple easily with aryl bromides and chlorides, without the aid of thallium or silver salts (entries 4 and 5).


Table 3.

As illustrated in Scheme 1, Q-Phos is an effective ligand for the palladium-catalyzed a-arylation of either diethyl malonate or ethyl cyanoacetate.3 Decarboxylation of the malonate products provides arylacetic acid derivatives that are synthetically useful intermediates. Alternatively, alkylation followed by decarboxylation provides a-arylcarboxylic acid derivatives that are also highly valued synthons. Arylations of diethyl malonate with chloroarene electrophiles proceed smoothly in the presence of Pd(dba)2 and Q-Phos, while reactions of chloro- or bromoarenes with ethyl cyanoacetate require Pd(dba)2 or [Pd(allyl)Cl]2 as Pd precursors, depending on the identity of the substrates. Simpler phosphines (such as P(t-Bu)3) may be used for the arylation of other alkyl malonates or alkyl cyanoacetates.


Scheme 1.

More recently, the Hartwig group demonstrated the first general method for the a-arylation of amides, via their zinc enolates.4 While zinc amide enolates are not common intermediates, they are easily generated by reaction of an alkali enolate with ZnCl2. Alternatively, they can also be generated via the reaction of activated Rieke® zinc with the requisite a-bromoamide, although this approach is limited to those bromoamides that are readily available. The use of zinc amide enolates instead of alkali metal enolates is preferred because the former exhibit greater functional group tolerance in coupling reactions.

As shown in Scheme 2, treatment of dialkyl acetamides or dialkyl propionamides with s-BuLi, followed by transmetalation with ZnCl2, generates an intermediate organozinc halide, which readily couples with aryl bromides in the presence of Q-Phos and Pd(dba)2 to give the a-arylamide. Electron-rich or electron-poor bromoarenes, vinyl bromides, and heteroaryl bromides are all reactive in the C–C bond-forming reaction. Finally, morpholine amides, which can behave similarly to Weinreb amides in their functional group manipulations,5 also undergo arylation.


Scheme 2.

We are pleased to add this versatile ligand to our growing portfolio of electron-rich phosphine ligands for cross-coupling reactions.

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Materials

     

References

  1. Kataoka, N. et al. J. Org. Chem. 2002, 67, 5553.
  2. Shelby, Q. et al. J. Am. Chem. Soc. 2000, 122, 10718.
  3. Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
  4. Hama, T. et al. J. Am. Chem. Soc. 2003, 125, 11176. (b) Hama, T. et al. J. Am. Chem. Soc. 2006, 128, 4976.
  5. (a) Kurosu, M.; Kishi, Y. Tetrahedron Lett. 1998, 39, 4793. (b) Badioli, M. et al. J. Org. Chem. 2002, 67, 8938. (c) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.

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