Synthesis in High Temperature Water and Hydrophosphination of Carbodiimides with Phosphine Boranes

John Milligan

Research Topic Seminar

Wipf Group Meeting- September 13, 2014

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PART I: SYNTHESIS IN HIGH TEMPERATURE WATER

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Water in organic synthesis

Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302

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Water in organic synthesis

Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.

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The critical point

http://www1.lsbu.ac.uk/water/phase.html

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Physical properties

Savage, P. J. of Supercritical Fluids 2009, 47, 407-414

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Previous work in SCW

Rebacz, N. A.; Savage, P. E. Phys. Chem. Chem. Phys. 2013, 15, 3562.

Leikoski, T. et al. Org. Process Res. Dev. 2005, 9, 629-633, 9.

Kus, S. N. Montash. Chem. 2010, 141, 307-310.

Kawahara, T. et al. Org. Process Res. Dev. 2013, 17, 1485-1491.

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Diels-Alder in SCW

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Proposed Diels-Alder in SCW

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Apparatus

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0

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0 50 100 150 200 250 300 350 400

Y

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Temperature (oC )

Yield vs. Temperature

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Retro-Diels-Alder

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Retro-Diels-Alder

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Oxidation

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Biomimetic Cyclizations

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Epoxide Rearrangement

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Conclusion

• Stable starting materials can be converted to stable products using the stainless steel tube

• Retro-Diels-Alder reactions of stable substrates work well

• Rearrangement of epoxides can be conducted

• Labile functionality is not well tolerated

• Apparatus material is important in expanding this work to more complex molecules

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PART II: HYDROPHOSPHINATION OF CARBODIIMIDES WITH PHOSPHINE BORANES

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Hydrophosphination

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Carbodiimide Hydrophosphination

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Substoichiometric base

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Substoichiometric base

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Phosphine Boranes

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Phosphine Boranes

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Hydrophosphinations

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Neat hydrophosphinations

Gaumont, A.-C. et al: Synlett 2005, No. 12, 1881-1884. J. Org. Chem. 2003, 68, 7016-7022. Chem. Commun. 2006, 3249-3251. Synthesis 2008, No. 19, 3121-3125.

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BIPI ligands

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BIPI Ligands

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Hydrophosphination Discovery

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Hydrophosphination Discovery

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Alkyne Hydrophosphination

Busacca, C. A. et al. Org. Lett. 2009, 11 (24), 5594-5597.

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Busacca’s hydrophosphination

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Busacca’s hydrophosphination

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Preliminary results

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• Only one phosphaguanidine borane prior to this work:

Mansfield, N. E.; Grundy, J.; Coles, M. P.; Avent, A. G.; Hitchcock, P. B. J. Am. Chem. Soc. 2006, 128, 13879-13893

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Nomenclature System

Mansfield, N. E.; Grundy, J.; Coles, M. P.; Avent, A. G.; Hitchcock, P. B. J. Am. Chem. Soc. 2006, 128, 13879-13893

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Comparison

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Carbodiimide preparation

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Results

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Phosphinite Borane

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Deprotections

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Air-stable HBF4 salts

Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3 (26), 4295-4298

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Product

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Divergent result

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Guanidinium Salts

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Feasible Oxidation?

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Oxidation Studies

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Catalytic applications

E. Rattanangkool

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A Thiourea mimic?

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Attempted asymmetric propargylation

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New strategy

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Metathesis approach

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Cyclic carbodiimides

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Cyclic carbodiimide

• Inexpensive materials

• One column chromatography

• >1 g prepared 62

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In situ CO2

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Conformation

• Equilibrating axially chiral enantiomers

• C-N=C=N-C dihedral angle: 68o

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Hydrophosphination

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Deprotection

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An improved carbodiimide?

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Successful tethers

Molina, P. et al. J. Org. Chem. 1996, 61, 4289-4299. 73

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Glycol-based tether

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A chiral constraint?

Molina, P. et al. J. Org. Chem. 1996, 61, 4289-4299.

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A chiral constraint?

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Chiral acetal

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Chiral acetal

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Alternative: A chiral methyl

Molina, P. et al. J. Org. Chem. 1996, 61, 4289-4299.

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A chiral methyl

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A chiral methyl

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Alternate approach

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Isolated by Molina

Isolated as dimer in low yield by JAM

Isolated as dimer in low yield by Molina

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Isolated by Molina

Isolated as dimer in low yield by JAM

Isolated as dimer in low yield by Molina

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An alterative cyclic system?

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Toward Bidentate phosphines

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Tethering

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Side Chain Modification

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Conclusion

• The scope of Busacca’s hydrophosphination was further explored

• The reaction is tolerant of a variety of carbodiimides

• Aryl phosphine boranes are not as effective as alkyl derivatives

• Acidic deboronations of phosphaguanidine boranes afford guanidinium borane salts, not deboronated products

• A cyclic carbodiimide was prepared, and underwent facile hydrophosphination with this method

• Modifications of the cyclic core have proven difficult to date

• Future directions include developing catalytic systems, preparing chiral phosphaguanidines, and crystallizing transition metal complexes

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Acknowledgements

• Dr. Wipf

• Wipf group past and present

• Eakkaphon “Onie” Rattanangkool

• Dr. Steve Geib

• Dr. Bhaskar Godugu

• A&S Graduate Fellowship

• Dr. Carl Busacca

• Dr. Chris Senanayake

• Cyrus Ramavarapu

• Others

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