Recent Advances of Alkyne Metathesis

Group Meeting

Timothy Chang

11-09-10

Fischer Carbyne and Schrock Alkylidyne

The Organometallic Chemistry of the Transition Metals, 4th Ed., Crabtree.Organotransition Metal Chemistry, From Bonding to Catalysis, Hartwig.

Fischer Schrock

Doublet Quartet

LX type X3 type

4e 6e

-1 -3

lone paircovalent

p-back bonding

3 covalents

Weak donor L Strong donor L

Group Orbitals of +CR Fragment

Carbyne Complexes, Fischer et. al. 1988, VCH

MOs of Fischer Carbyne

Carbyne Complexes, Fischer et. al. 1988, VCH

Group Orbitals of L3M- Fragment

Encyclopedia of Inorganic Chemistry, Electronic Structure of Organometallic Compounds,

Albright, T. A.

Molecular Orbitals of L3M(CR)

Carbyne Complexes, Fischer et. al. 1988, VCH

A Brief History of Alkyne Metathesis

Pennellar, F.; Banks, R. L.; Bailey, G. C. J. Chem. Soc., Chem. Commun. 1968, 1548.

Mortreux, A.; Blanchard, M. J. Chem. Soc., Chem. Commun. 1974, 786.

Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592.For an account, see Schrock, R. R. Polyhedron, 1995, 14, 3177.

Catalyst Deactivation by Dimerization and Ring Expansion

Zhang, W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93.

“Pseudopoisoning” Effect

Zhang, W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93.

Preparation of (Me3CO)3W(CCMe3)

Schrock et. al. J. Am. Chem. Soc. 1981, 103, 3932.Zhang, W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93.

Application to RCAM

Fürstner et. al. Angew. Chem. Int. Ed. 1998, 37, 1734 and J. Am. Chem. Soc. 1999, 121, 11108.

Thioether, basic nitrogen containing functional groups are not compatible.Tolerate acidic proton of a secondary amide.

Curious Effect of Halogenated Solvents

Fürstner et. al. Chem. Eur. J. 2001, 7, 5299 and J. Am. Chem. Soc. 1999, 121, 9453

Secondary amide is not tolerated.

Major Components of the Molybdenum Species

Schrock et. al. J. Am. Chem. Soc. 1985, 107, 5987 Polyhedron 1995, 15, 3177

Why is 3 not catalytically active?Why are terminal alkynes not viable substrates?

“Deprotiometallacyclobutadiene”

1 : 2 not activeAr = 3,5-xylyl

Cross Metathesis

Fürstner , A., Mathes, C. Org. Lett. 2001, 3, 221

1

Cross Metathesis

Fürstner , A., Mathes, C. Org. Lett. 2001, 3, 221

1

Application of RCM and RCAM to Macrocyclization

RCM RCAM

Fürstner et. al. Chem. Eur. J. 2003, 7, 5299.

Schinzer et. al. ACIEE 1997, 36, 523.

Reductive Recycle Strategy for Catalyst Preparation

Moore et. al. Org. Syn. 2007, 84, 163.

Ar = 3,5-xylyl

- Active catalyst is generated in the presence of various phenols.- Electron-deficient ligands make the catalysts more active e.g. p-nitrophenol (low cost)- Catalyst is active in MeCN even though it is a coordinating solvent.- Secondary amide and thiophene containing molecules can be used.- Bulky ligand is not required. Apparently electronic factor dominates.- Bulky ligands slows down both dimerization and metathesis presumably.

Effects of Alkyl Substituent and Ligand

Moore et. al. J. Am. Chem. Soc. 2004, 126, 329.

R = Me gives polybutyne

Equilibrium ratio of 13:14 = 2:3 (established from both 13 and 14, respectively)

R = Et

5

Optimal R = Et

Optimal Ligand = p-nitrophenol

(cheaper)

Ar = 3,5-xylyl

Homodimerization Substrate Scope

a Closed system, d8-toluene, 20 °C, t1/2 is the time required for the reaction to reach 50% of final constant ratio of 10 to 12. b Open driven condition, solvent 1,2,4-trichlorobenzene, 30 °C, 22 h, 1 mm Hg, yield based on isolated product. c Ligand A ) R,R,R-trifluoro-o-cresol. d Ligand B ) p-nitrophenol.

R = Et

5Ar = 3,5-xylyl

Solvent Effect and Precipitation Strategy

Conversion CHCl3, Toluene: 100% (0.5 h) CH3CN, THF: 76% (8 h)Acetone: 40% (catalyst decomposition)DMF, MeOH: 0%

Precipitation strategy can be utilized to drive the equilibrium towards desired product such as 7.Aprotic, non-coordinating solvents are preferred.

R = Et

5Ar = 3,5-xylyl

Moore et. al. J. Am. Chem. Soc. 2004, 126, 329.

Preparation of Shape-Persistent Macrocycles by PPT Strategy

Zhang, W.; Moore, J. S. J. Am. Chem. Soc. 2004, 126, 12796.

Catalyst Prepared from Nitrides by Metathesis with Alkynes

Zhang, W.; Moore, J. S. Adv. Synth. Catal. 2007, 349, 93.

- 36 and 38 are preferred thermodynamically.- The formation of 38 is irreversible.- Idea: in situ generation of catalyst by metal nitride/metal alkylidyne interconversion

One major reason that MeCN cannot be used

Johnson et. al. J. Am. Chem. Soc. 2006, 128, 9614. Johnson et. al. Inorg. Chem. 2005, 44, 9140.

Schrock, Organometallics 1986, 5, 398.

Development Towards a Robust and Practical Precatalyst

Fürstner et. al. J. Am. Chem. Soc. 2009, 131, 9468.

distorted square pyramidal

Scope

Fürstner et. al. J. Am. Chem. Soc.2009, 131, 9468

11 can be weighed in air and used under dry air (need increased loading)

Incompatible: epoxide, aldehyde, acyl chloride

Improvements on Triphenylsilanolate Bound Mo (Pre)Catalyst

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 11045.

Typical Reaction Conditions for Homodimerization, CM, RCAM(A) 15 (10 mol %), MnCl2 (10 mol %), MS 5 Å, toluene, 80 °C, 30 min, then

addition of the substrate and reaction at 80 °C or 100 °C (for CM).

(B) 24 (2 mol %), toluene, ambient temperature, MS 5 Å.

(C) 25 (5 mol %), MnCl2 (5 mol %), toluene, 80 °C, 30 min; then addition of the substrate and MS 5 Å, and reaction at ambient temperature.

15 is stable on bench top for storage.

Scope

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 11045.

Incompatible with aldehyde. Previous stoichiometric experiment showed its conversion to nitrile.

Roles of Molecular Sieve

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 11045.

MS removes butyneMS helps liberate Et2O

3 Å MS has no sig. effect (i.e. not equilibrium effect of H2O)

Probing the Active Mo Species

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 11045.

trace

Hypotheses:“The small amounts of alkylidynes, such as 16, formed in the mixture must be superbly active”“12.L acts as a reservoir (slow release) (still show catalytic activity at 80 oC for days)

The hypotheses were tested using 19 and 24.

Preparation of Molybdenum Alkylidyne Complexes

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 11045.

An Extraordinary Active Metathesis Catalyst

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 11045.

Equilibrium reached at ~ 25 min

Application of RCAM to the Synthesis of Lactimidomycin

1.2 g scale84%

Key steps: Ring closing alkyne metathesis and trans-hydrosilylation

Lactimidomycin

Seven sp2 C in a12-membered lactone

Fürstner et. al. J. Am. Chem. Soc. 2010, 132, 14064.

Imidazolin-2-iminato Tungsten Catalyst

Tamm et. al. Angew. Chem. Int. Ed. 2007, 46, 8890.

hexane (4.5 mM)2 h, 95%

Conclusion

- New (pre)catalysts are much more functional group tolerant and efficient.

- Bench top stable pre-catalyst has emerged (silanolate bound Mo complexes).

- The yields of cross-metathesis are generally moderate.

- RCAM and homodimerization are relatively mature.

- Three ways to drive the equilibrium of metathesis:

(1) reduced pressure, (2) precipitation and (3) molecular sieve

- Mechanism of some pre-catalysts is still unknown (tris-amido Mo complex).

- Promising in the area of ADIMET and Shape Persistent Macromolecules.

Alkyne Metathesis, see Zhang, Moore Adv. Synth. Catal. 2007, 349, 93. RCAM, see Fürstner, Davies Chem. Commun. 2005, 2307.Carbyne Complexes, Fischer et. al. 1988, VCH VerlagsgesellschaftHandbook of Metathesis: Catalyst Development, Grubbs, Ch 1.11

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