Rethinking cross-coupling:

Enantiospecific sp2-sp3 coupling

Souvik Rakshit

Burke group Literature Seminar

July 19, 2014

A. Bonet, M. Odachowski, D. Leonori, S. Essafi, V. K. Aggarwal; Nature Chem. 2014, 6, 584–589

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Pd-catalyzed sp2-sp3 coupling

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Biscoe (2013)

Pd-catalysed cross-coupling reactions between isolable, optically active organometallic

nucleophiles and aryl halides

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E+

E

E

H. Sun, D.G. Hall; Nature Chem. 2014, 6, 562.

V. K. Aggarwal et al. The Chemical Record 2009, 9, 24.

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Related SEAr of electron rich aromatic group with achiral boranes

A. B. Levy; J. Org. Chem. 1978, 43, 4684 A. Suzuki et. al. Synthesis 1979, 146.

• Handling air-sensitive boranes

• Creating stereo-defined boranes

• Issue as to which group will migrate in non-symmetrical boranes

A. B. Levy et al. Tet. Lett. 1979, 20, 2313.

Difficulty associated with

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Synthesis of enantioenriched secondary and tertiary boronic esters

V. K. Aggarwal et al. Angew. Chem. Int. Ed. 2007, 46, 7491; Nature 2008, 456, 778; Angew. Chem. Int. Ed. 2010, 49, 5142;

J. Am. Chem. Soc. 2013, 135, 16054.

One-pot lithiation/borylation of Hoppe-type carbamates

Lithiation/borylation of enantioenriched secondary

carbamates.

R = BnCH2, R1 = Me, R2 = Et, R3 = pin

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Synthesis of enantioenriched secondary and tertiary boronic esters

Readily available

Stable

High enatiopurity

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V. K. Aggarwal, et al. J. Am. Chem. Soc. 2011, 133, 16794; Chem. Sci. 2013, 5, 602.

Aliphatic electrophilic substitution at sp3 carbon

Optimized Conditions for stereospecific sp2-sp3 coupling

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10

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Solvent effect

V. K. Aggarwal Chem. Sci. 2013, 5, 602–607.

THF: SE2inv dominate

MeOH: SEAr dominate due to involvement of

cationic intermediate

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Effect of substituent

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Effect of substituent

Berionni, G., Maji, B., Knochel, P., Mayr, H. Chem. Sci. 2012, 3, 878.

2 and 4-methoxyphenyllithium were not effective, whereas 3-methoxyphenyllithium was.

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Post-modification of functional group

Suzuki cross-couplings of aryltrimethylammonium salts

Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 6046.

Removal of dialkylamino-substituents from aromatic rings

Paras, N., Simmons, B.; MacMillan, D.W. C. Tetrahedron 2009, 65, 3232.

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Summary

A general method for coupling electron-rich aromatic/ heteroaromatic compounds

with enantioenriched secondary and tertiary boronic esters.

This methodology, which uses simple, readily available reagents, no transition

metals and user-friendly conditions, shows broad scope in the boronic esters and

shows complete stereospecificity.

Although its virtues are certainly more numerous, the method is not without its

limitations.

• The aryl halide coupling partner is limited to electron-rich or heteroaryl species

• The use of aryl lithium reactants, which are both strong bases and

nucleophiles, limits the types of functionality that can be tolerated under these

reaction conditions.