Intramolecular Hydrogen Transfer Reactions Catalyzed by Pentamethylcyclopentadienyl Rhodium and Cobalt Olefin Complexes: Mechanistic Studies

Abstract

The mechanism of intramolecular transfer dehydrogenation catalyzed by [Cp^*M(VTMS)₂] (1, M=Rh, 2, M=Co, Cp* = C₅Me₅, VTMS = vinyltrimethylsilane) complexes has been studied using vinyl silane protected alcohols as substrates. Deuterium-labeled substrates have been synthesized and the regioselectivity of H/D transfers investigated using ¹H and ²H NMR spectroscopy. The labeling studies establish a regioselective pathway consisting of alkene directed α C–H activation, 2,1 alkene insertion, and finally β-hydride elimination to give silyl enol ether products.

Graphical abstract

The mechanism of intramolecular transfer dehydrogenation catalyzed by [Cp*M(VTMS)₂] (M=Rh, Co, Cp* = C₅Me₅) complexes has been studied using vinyl silane protected alcohols as substrates. Using deuterium-labeled substrates, the regioselectivity of H/D transfers was investigated using NMR spectroscopy. These studies establish a regioselective pathway involving alkene directed α-C–H activation, 2,1 alkene insertion, and finally β-hydride elimination to give silyl enol ether products

Introduction

C–H activation/functionalization reactions using transition metal catalysts have received much attention in recent years, resulting in a burgeoning field of new synthetic methods.[1] Initial efforts investigated stoichiometric C–H activation reactions mediated by a transition metal. This early work has blossomed into new catalytic processes for the formation C–C, C–O, C–N, and C–X, bonds.[2] Such processes are finding multiple applications in the synthesis of natural products, pharmaceuticals, and agrochemicals.[3,4]

An alternate, less common strategy to employ C-H activation chemistry in synthesis is to convert saturated linkages to alkenes, R-CH₂-CH₂-R′ to R-CH=CH-R′.[5] Development of new routes to alkenes is attractive since alkenes represent a privileged class of substrates, readily converted into a myriad of other functional groups. Electrophilic additions, oxidations, and olefin metatheses represent just a few examples of the versatile transformations possible using alkenes. As with C–H to C–Y conversions, a dehydrogenation route to alkenes is attractive in that the method can potentially eliminate the need for pre-installed functional groups and the use of harsh reagents (e.g., strong base or acid).

While hydrocarbon cracking using a zeolite catalyst is a common industrial method for the production of short chain (<C₆) alkenes, high temperatures are required for this “acceptorless” dehydrogenation and are not compatible with synthetic applications.[6] The hydrogen transfer methodology is most commonly employed to carry out dehydrogenations in solution under mild conditions. Transfer dehydrogenation of alkanes utilizing various olefins as acceptors has seen extensive development.[7] Iridium pincer complexes have emerged as the most robust and widely used catalysts in this regard. Catalysts are typically screened using t-butyl ethylene as the acceptor for the dehydrogenation of cyclooctane to cyclooctene, ΔG = −6 kcal/mol(Scheme 1). Iridium pincer catalysts have achieved turnover numbers of up to 6000 for this transformation.[7,8]

Scheme 1.

Dehydrogenation of cyclooctane with t-butylethylene.

Despite the numerous studies of transfer dehydrogenation of simple alkanes, this method has seen little application for the preparation of functionalized olefins. [9,10] However, a recent report has expanded this work to simple heterocycles. Huang and coworkers have developed a new iridium pincer complex capable of dehydrogenating heterocycles using t-butylethylene as the hydrogen acceptor. Additionally, two significant advances in the dehydrogenation of functionalized substrates utilizing Pd salts as catalysts have been reported. Yu and coworkers have shown in a series of stoichiometric and catalytic studies that the use of an appropriate directing group and benzoquinone as acceptor can promote a C–H activation/β-hydride elimination sequence for the directed installation of an alkene (Scheme 2). [11] Separately Stahl has shown in the absence of a traditional directing group, C–H activation followed by β-hydride elimination can be an effective strategy for constructing alkenes (Scheme 3). [12,13] In a series of elegant studies the authors demonstrated Pd^II salts coupled with O₂ as the oxidant (acceptor) to be an effective system for the aerobic dehydrogenation of cyclic ketones to generate α,β unsaturated ketones and phenols. [14]

Scheme 2.

Yu’s ligand-directed dehydrogenation

Scheme 3.

Stahl’s aerobic dehydrogenation

Our work in this area has stemmed from early investigations using [Cp^*M(VTMS)₂] (1, M=Rh, 2, M=Co) (VTMS = vinyltrimethylsilane) complexes as catalysts for H/D exchange reactions in aromatic solvents and for hydroacylation of olefins. [15,16] The use of the labile bulky alkene, trimethylvinylsilane, allowed facile access to the reactive 16-electron fragment, Cp^*M(VTMS), for C–H activation in these reactions. These complexes have been successfully applied to intramolecular transfer dehydrogenation reactions using protected alcohols and cyclic amines (Schemes 4 and 5). In this approach to transfer dehydrogenation, vinyl silane protecting groups are readily installed on the desired substrates and used as hydrogen acceptors. A series of studies in this area has resulted in new base-free, and mild routes to silyl enol ethers [17], 1,2-diheteroatom substituted olefins [18,19], and cyclic enamines. [20] Similar chemistry has been previously reported by Bradley using Cp*M(C₆H₆), M = Co.[21]

Scheme 4.

Synthesis of silyl enol ethers and 1,2-diheteroatom substituted olefins via transfer dehydrogenation.

Scheme 5.

Synthesis of enamines via transfer dehydrogenation

As part of these studies, we proposed a preliminary mechanism for intramolecular transfer dehydrogenation using the Cp*Rh(VTMS)₂ complex as shown in Figure 1. [18] The catalytic cycle was entered by displacement of the labile VTMS ligand by excess substrate to yield 3. Alkene loss generates a 16-electron complex 4 that undergoes activation of the proximal C–H bond via oxidative addition to give 5. Then a series of migratory insertion, β-hydride elimination, and reductive elimination reactions (via 6 and 7) generate the Rh-bound product 8. Finally, displacement of product by another equivalent of substrate closes the catalytic cycle. An analogous mechanism was proposed for the transfer dehydrogenation of protected amines to generate enamines using Cp*Co(VTMS)₂ complexes. In this report we describe experiments aimed at elucidating the full mechanistic details of these transformations using a series of isotopically labeled substrates.

Figure 1.

Proposed mechanism for the intramolecular hydrogen transfer reactions

Results and Discussion

Regioselectivity Studies

To evaluate the regioselectivity of hydrogen transfer in conversion of 9 to 10 (Scheme 6) two deuterium-labeled substrates were synthesized and submitted to the optimized reaction conditions. Vinyl silane-protected alcohols labeled with deuterium at the α(11) and β(13) positions of the ethoxy group were used and the regioselectivity determined by ¹H and ²H NMR spectroscopy (Scheme 7, a and b).

Scheme 6.

Representative example of transfer dehydrogenation with 1 or 2

Scheme 7.

Hydrogen transfer reactions of deuterium-labeled 11 and 13

After subjecting 11 to the optimized reaction conditions using either rhodium complex 1 or cobalt complex 2, 12 was observed as the major d₂ product (Scheme 7, a). Similarly, the isotopologue 13 led to 14 as the major d₃ product (Scheme 7, b). Inspection of the ¹H NMR spectra of 12 and 14 support the labeling patterns shown (Figure S1). The integrals of the terminal vinyl signals and the methylene signal of 12 indicate little or no deuterium incorporation (but see below). Furthermore, the methylene resonance is now a broad triplet (J=7.5 Hz), due to coupling to CH₂D, and the methyl group appears as a triplet of triplets (J=7.8 Hz and 2 Hz) resulting from vicinal coupling to the methylene unit and geminal coupling to one deuterium. Likewise, the spectrum of 14 shows no evidence for significant incorporation of deuterium into either the methine group or the β-methyl group, which appears as a broad doublet (J = 7.5 Hz) due to coupling with a single vicinal H. The methylene group is now an unresolved multiplet integrating for ca. 1H. As captured in Scheme 7, a and b, the primary modes of migration are from the α-methylene site of 11 to the β-methyl site in 12 and from the β-methyl site in 13 to the β-methylene site in 14.

The labeling experiments implicate a regioselective mechanism for hydrogen transfer that follows one of the two pathways (A or B) outlined in Scheme 8. Initial C–H activation can occur via alkene coordination and oxidative addition of either the α or β C–H bond. In pathway A activation of the α C–H bond followed by 2,1 alkene insertion leads to a 5-membered metallacyclic intermediate, 15. β-Hydride elimination and C–H reductive elimination generates the observed product. In pathway B, activation of the β C–H bond followed 1,2 alkene insertion leads to a 7-membered metallacyclic intermediate, 16, which can proceed to product by β-elimination and reductive elimination. Below, we outline additional labeling experiments that are consistent with pathway A.

Scheme 8.

Possible pathways for regioselective hydrogen transfer illustrated for 11.

Isotope Scrambling

α-deuterium labeled substrate

Monitoring the reaction (a) in Scheme 7 at early conversions reveals extensive H/D scrambling in the starting material, 11. Results in the case of the cobalt complex 2 are summarized in Scheme 9. Even at short reaction times (15min) H/D scrambling has occurred to produce a ca. 1:1 ratio of 11 and scrambled product 11s.

Scheme 9.

H/D scrambling results observed with 11

Similar reactivity is observed with catalyst 1 (Rh) under optimized reaction conditions (140°C), albeit at a reduced rate (see Figure 2). After 0.5h, H/D scrambling is observed in the starting material at the site α to oxygen, evident by the appearance of a multiplet at 3.6 ppm in the ¹H NMR spectrum. The signal at 3.6 ppm continues to grow and reaches a maximum at ca. 1.5h. At 2.5 h the 3.6ppm signal begins to diminish as hydrogen transfer product, 12, begins to accumulate as clearly seen by the appearance of the vinyl resonance at 6.3ppm. After 18h, all of 11 and 11s have been converted to 12. The scrambling results for both the cobalt and rhodium systems show that this process occurs faster than formation of silyl enol ether product, 12. These results clearly suggest that pathway A (Scheme 8) operates and that once intermediate 15 forms it returns to starting material 11 faster than formation of 12. [21]

Figure 2.

¹H NMR spectra for conversion of 11 using catalyst 1

β-deuterium labeled substrate

Importantly, in contrast to the α-deuterium labeled substrate 11, H/D scrambling was not observed in starting material 13 under reaction conditions, as shown in scheme 10.

Scheme 10.

Hydrogen transfer with β-deuterium-labeled substrate.

As with 12 (scheme 8), two analogous pathways could result in regioselective formation of the observed product, illustrated in scheme 11 for substrate 13.

Scheme 11.

Possible pathways for regioselective hydrogen transfer of 13.

If pathway B were viable, oxidative addition β to oxygen would lead to metallacycle 18, which would be expected to yield H/D scrambled product 13s as shown. The conspicuous absence of this product strongly suggests that the mechanism does not proceed via this path. These experiments are consistent with pathway A outlined above (Schemes 8 and 11), comprising initial oxidative addition α to oxygen, followed by 2,1-insertion producing a 5-membered metallacyclic intermediate.

A scrambling process can, however be observed by ²H NMR analysis following formation of 14. Upon prolonged heating (~18 hours) with catalyst 1 or 2, ²H signals begin to appear in the Si–methyl positions, while ¹H signals grow into the β-vinyl positions (Scheme 12).

Scheme 12.

H/D Scrambling of 14 with catalyst 1.

This product must ultimately stem from a silyl enol directed C–H activation mechanism as shown in Scheme 13, in which the product alkene directs oxidative addition to the C–H bonds α to Si producing intermediate 19. Collapse of this product can result in ²H incorporation into the Si-methyl group giving 14s.

Scheme 13.

α-Si-Me Activation in 14 by 1 or 2

1,2 Diheteroatom substrates

In an earlier report using a similar hydrogen transfer scheme we observed the formation of 1,2 diheteroatom-substituted olefins, a particularly difficult class of substrates to synthesize via direct methods. [19] Our mechanistic investigations next looked at this class of substrates by focusing on similar H/D labeling experiments used above. At the outset we envisioned the same two possible mechanisms (Scheme 14, pathways A and B) for the hydrogen transfer reaction with 1,2 diheteroatom substrates. However, in contrast to 9, in this class of substrate both pathways involve C–H activation α to a heteroatom. Thus these substrates provide an opportunity to investigate the importance of alkene chelation in regioselective transfer hydrogenation. Deuterium isotope labeling of the α C–H bonds provided a useful probe for distinguishing between these mechanistic pathways.

Scheme 14.

Proposed Pathways for Hydrogen Transfer using 1,2 Diheteroatom Substrates

Submitting deuterium-labeled substrate 20 to reaction conditions too mild for hydrogen transfer to occur (Rh catalyst 1, 70 °C) resulted in significant H/D scrambling exclusively between the labeled C–D bond β to Si and the terminal vinyl positions as depicted in Scheme 15. After 140 minutes scrambling can be observed by the appearance of new ¹H NMR resonances at 3.64 ppm (OCH₂ and OCHD) accompanied by a change in the coupling patterns of the vinyl signals.

Scheme 15.

H/D scrambling observed with 20

When 20 was exposed to hydrogen transfer conditions (100 °C, 4.5 h) 93% conversion to the silyl enol ether was observed (Scheme 16). Two stereoisomers were observed in the ¹H NMR spectrum consistent with the trans and cis alkene products in an 8:1 ratio, respectively. Both the trans and cis enol ether products as well as the remaining starting material have undergone H/D exchange at the alpha C–H bond, results similar to that observed at 70 °C (Scheme 12).

Scheme 16.

Hydrogen transfer reaction with 20

The ¹H NMR spectra of 21/22 (d₂ and unlabeled) are shown in Figure 3 and clearly illustrate deuterium incorporation within the methyl group. The coupling pattern of the CH₂ protons in d₂- 21, centered at 0.58 ppm, has changed (compared to that of unlabeled 21 and 22) to a broadened triplet due to coupling to the terminal CH₂D group. The methyl resonance, which is centered at 0.94 ppm, shows a coupling pattern which consists primarily of a triplet of triplets (vicinal coupling to CH₂(²J_HH = 8 Hz) and a geminal coupling (¹JHD = 1.8 Hz) to one deuterium atom). Transfer dehydrogenation performed with Co catalyst 2 provided identical results. While there is minor overlap between the trans and cis products the spectra show no evidence of deuterium incorporation into the alpha position of the silyl ethyl chain.

Figure 3.

Comparison of ¹H NMR spectra of d₂-21/22 with unlabeled 21/22

These experiments support a hydrogen transfer mechanism involving C–H activation at the position α to the siloxy group via pathway A, Scheme 13. Given that the C-H bonds α and β to the siloxy group have relatively similar bond strengths, the regioselective activation of the α C-H bond must be the result of alkene chelation directing activation of this bond and formation of a five-membered chelate. The H/D scrambling noted in 20 prior to product formation establishes that once the five-membered metallacycle is formed it returns to 21 faster than forming product, similar to the mechanism of 11 discussed above.

Summary/Conclusion

After a series of deuterium labeling studies we have established a general mechanism for hydrogen transfer with catalysts 1 and 2. These results implicate a highly regioselective pathway outlined in Figure 4 below. Following the dissociation of VTMS groups by substrate to give 23, an alkene directed, reversible α C–H activation occurs to produce intermediate 24. This step is followed by 2,1 alkene insertion to generate a 5-membered metallacycle 25. β-Hydride elimination to give 26 and C–H bond-forming reductive elimination leads to the product-bound complex 27. The H/D scrambling observed after product formation proceeds through a similar intermediate 28 in a similarly regioselective manner, again illustrating the reversibility of these steps. The overall transformation is thermodynamically favored via the formation of an enol or enamine product.

Figure 4.

General Mechanism Established for Hydrogen Transfer Catalyzed by 1 or 2

Studies with 1,2 diheteroatom substrates have shown the high regioselectivity observed in hydrogen transfer reactions with 1 and 2 is a result of both the alkene directing group and high preference for formation of a 5-membered metallacycle. Despite the similar bond dissociation energies of the α, β C–H bonds accessible in this system, both 1 and 2 prefer the pathway proceeding through α C–H activation.

Appendix A. Supplementary Data

Experimental details and supplementary data associated with this article can be found in the online version, at xxxx.