From the Glovebox to the Benchtop: Air-Stable High Performance Molybdenum Alkylidyne Catalysts for Alkyne Metathesis

Abstract

Molybdenum alkylidynes endowed with tripodal silanolate ligands belong to the most active and selective catalysts for alkyne metathesis known to date. This paper describes a new generation that is distinguished by an unprecedented level of stability and practicality without sacrificing the chemical virtues of their predecessors. Specifically, pyridine adducts of type 16 are easy to make on gram scale, can be routinely weighed and handled in air, and stay intact for many months outside the glovebox. When dissolved in toluene, however, spontaneous dissociation of the stabilizing pyridine ligand releases an active species of excellent performance and functional group tolerance. Specifically, a host of polar and apolar groups, various protic sites, and numerous basic functionalities proved compatible. The catalysts are characterized by crystallographic and spectroscopic means, including ⁹⁵Mo NMR; their activity and stability are benchmarked in detail, and the enabling properties are illustrated by advanced applications to natural product synthesis. For the favorable overall application profile and ease of handling, complexes of this new series are expected to replace earlier catalyst generations and help encourage a more regular use of alkyne metathesis in general.

Figure 1

Selection of contemporary alkyne metathesis catalysts and (semi)stable versions thereof; the stabilizing ligand/matrix is shown in blue

Figure 2

Prototype molybdenum alkylidyne tris-silanolate catalysts; attempted stabilization by ligation to pyridine. The parent complexes 1 differ from the “canopy” variant 2 in the curvature of the first coordination sphere about the metal center (see the Inset and the Text).

Scheme 1. Alternative Catalyst Design Based on a Tethered Triphenol Ligand Scaffold, Exemplified by an N-Tethered Variant (Z = N, R = H)

Scheme 2. Sterically Demanding N-Tethered Trisphenol Ligand 7a Fails To Afford a Tripodal Catalyst

Figure 3

Structure of complex 10 in the solid state; all H-atoms, except the phenolic −OH, and solute benzene in the unit cell were removed for clarity. The full structure is contained in the Supporting Information.

Figure 4

Design concept revisited.

Scheme 3. Preparation of Ligands and Catalysts

Reagents and conditions: (a) 1,3-propanediol, pTsOH (3 mol%), toluene, reflux, 81% (R = H), 72% (R = Me); (b) (i) i-PrMgBr (0.4 equiv.), n-BuLi (0.8 equiv.), THF, 0°C; (ii) Ph₂Si(OMe)₂, 0°C → RT, 85% (R = H), 70% (R = Me); (c) HCl (6 M), THF, 0°C, 92% (R = H), 94% (R = Me); (d) NH₄OAc, NaBH(OAc)₃, THF; (e) NaOH (2 M), THF, 60% (over two steps, R = H), 65% (over two steps, R = Me); (f) 9, toluene, 94% (R = H), 98% (R = Me); (g) pyridine, CH₂Cl₂, 88% (R = H), 77% (R = Me); (h) PMe₃, CH₂Cl₂, 92%; the indicated scales refer to the single largest batch for R = Me (unless otherwise specified).

Figure 5

Structure of ligand 14b in the solid state; all H-atoms were removed for clarity, except those of the Si–OH groups, which mutually engage in hydrogen bonding interactions (2.03 Å) and stabilize the favorable “upward/inward” conformation.

Figure 6

Truncated structure of complex 15b in the solid state; the two phenyl rings on each of the Si-atoms were removed for clarity, and solute solvents and the second independent molecule in the unit cell are not shown either. The full structure is contained in the Supporting Information.

Figure 7

Truncated structure of pyridine adduct 16b in the solid state; the two phenyl rings on each of the Si-atoms were removed for clarity. The full structure is contained in the Supporting Information.

Figure 8

Top: Photograph of a sample of the crystalline pyridine adduct 16b; aromatic region of the ¹H NMR spectrum ([D₈]-toluene, 253 K) of this sample after storage in air at ambient temperature for 8 months, showing only trace impurities caused by hydrolysis (for the full spectra, see the Supporting Information). Bottom: approximate lifetimes of other molybdenum alkylidyne catalysts when stored in air.

Scheme 4. Distinct Behavior of Tripodal Molybdenum Alkylidyne Silanolate Complexes Vis-à-Vis 2-Butyne

Scheme 5. Model Alkyne Metathesis Reaction Used for Benchmarking Purposes

Figure 9

Consumption of alkyne 21 with time as monitored by ¹H NMR spectroscopy in different benchmarking experiments using 5 mol% of the respective catalyst in [D₈]-toluene. (A) Comparison of the tripodal complex 15a and the derived pyridine adduct 16a at 25 °C; (B) comparsion of complexes 15b and 17, differing only in the substituents at the silicon linkers at 0 °C; (C) comparison of the canopy catalyst 2a and complex 17b at −20 °C.

Scheme 6. Homo-metathesis Reactions of Functionalized Substrates Using Complex 16a as the Catalyst at 50°C, unless Stated Otherwise; the Chosen Catalyst Loading Is Color-Coded (Blue = 2 mol%; Red = 5 mol%)

With added BPh₃ (5 mol%). Using the free complex 17 instead of adduct 16a. At 110°C. With 7 mol% of catalyst at 110 °C. At 90°C. At 100°C. At RT. With MS 4Å (instead of 5Å).

Scheme 7. Macrocycles by Ring Closing Alkyne Metathesis

All reactions were performed in toluene (2 mM) in the presence of MS 5Å using the indicated catalyst; note that complex 16a was weighed, handled and stored in air. All substrates were carrying methyl caps on the triple bonds. A modified “expedited” workup was necessary to obtain pure samples; see the Text.

Figure 10

Unreactive substrates.

Scheme 8. Applications to Advanced Intermediates of Previous Natural Product Syntheses; Note That Complex 16a Was Weighed, Handled and Stored in Air

16a (5 mol%), 60°C, toluene, MS 5Å, 81%. 16a (5 mol%), 50°C, toluene, MS 5Å, 65%. 16a (10 mol%), 60°C, toluene, MS 5Å, 94%. 16a (30 mol%), 110°C, toluene, MS 5Å, 71%. 16a (30 mol%), 110°C, toluene, MS 5Å, 81%.

Scheme 9. Concurrent Formation of Two Macrocycles