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Published in final edited form as: J Am Chem Soc. 2021 Aug 20;143(34):13507–13512. doi: 10.1021/jacs.1c07230

Conversion of Primary Alcohols and Butadiene to Branched Ketones via Merged Transfer Hydrogenative Carbonyl Addition-Redox Isomerization Catalyzed by Rhodium

Brian J Spinello 1, Jessica Wu 1, Yoon Cho 1, Michael J Krische 1
PMCID: PMC8739284  NIHMSID: NIHMS1767391  PMID: 34415159

Abstract

The first examples of rhodium-catalyzed carbonyl addition via hydrogen auto-transfer are described, as illustrated in tandem butadiene-mediated carbonyl addition-redox isomerizations that directly convert primary alcohols to isobutyl ketones. Related reductive coupling-redox isomerizations of aldehyde reactants mediated by sodium formate also are reported. A double-labelling crossover experiment reveals the kinetic rhodium alkoxide enacts redox isomerization without dissociation of rhodium at any intervening stage.

Graphical Abstract

graphic file with name nihms-1767391-f0003.jpg

Metal-catalyzed carbonyl reductive coupling has emerged as an important method for C-C bond formation.1 These processes unlock the possibility of replacing stoichiometric organometallic reagents with safer and more tractable pronucleophiles, including abundant π-unsaturated feedstocks2 such as α-olefins,3 styrene,4 acetylene,5 and butadiene.6 Despite the promise of this approach, catalytic reactions of this type often require reductants that are not ideal (Mn, Zn, Et3B, Et2Zn, HSiR3).1 Consequently, work from our laboratory has focused on the use of feedstock reductants (H2, 2-PrOH, HCO2H) in metal-catalyzed carbonyl reductive coupling.7,8d Additionally, we have developed a unique class of hydrogen auto-transfer processes in which alcohols serve dually as reductants and carbonyl proelectrophiles, thus enabling direct conversion of lower alcohols to higher alcohols.7,8d Given the commercial significance of ketones across diverse chemical industries, and the fact that classical methods for their convergent construction rely on premetalated reagents,9,10 efforts were made to exploit hydrogen transfer in metal-catalyzed ketone syntheses beyond premetalated reagents or metallic reductants (Figure 1). Preexisting methods of this type include hydroacylation (which typically requires β-chelating groups to suppress decarbonylation),11,12 “oxa-Heck” reactions (which are restricted to aryl transfer),13–15 two reports of the reductive coupling of styrenes with anhydrides4a,c and, finally, recently reported formate-mediated reductive coupling-redox isomerizations of aldehydes and vinyl halides16a or triflates.16b Here, we report a method for the direct redox-neutral conversion of primary benzylic or aliphatic alcohols and butadiene (12 x 106 tons/year) to branched ketones via merged transfer hydrogenative carbonyl addition-redox isomerization.17,18,19,20 These processes represent the first examples of rhodium-catalyzed carbonyl addition via hydrogen auto-transfer.7,8c

Figure 1.

Figure 1.

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Classical methods for convergent ketone construction and convergent catalytic ketone syntheses beyond premetalated reagents or metallic reductants.

In an initial experiment, 3-methoxybenzyl alcohol 1a (100 mol%) and butadiene 2a (500 mol%) were exposed to K2CO3 (20 mol%) in the presence of the catalyst derived from Rh(acac)(CO)2 (5 mol%) and PPh3 (11 mol%) in PhCl (0.2 M) at 130 °C.16 The desired branched ketone 3a was isolated by flash column chromatography in 13% yield along with a substantial quantity of unreacted alcohol 1a (Table 1, entry 1). It was postulated that a cationic rhodium catalyst might facilitate β-hydride elimination of the transient rhodium alkoxide. Indeed, upon evaluation of different rhodium precatalysts (Table 1, entries 1-5), a 70% isolated yield of 3a was obtained using Rh(cod)2BAr4F (Table 1, entry 5). The yield of 3a was further improved to 87% by increasing the loading of K2CO3 (50 mol%) (Table 1, entry 6). Deviation from the latter conditions did not enhance the yield of 3a (Table 1, entries 7-11). In particular, omission of K2CO3 resulted in a significantly lower yield of 3a (Table 1, entry 7). The importance of base is also reflected by the sensitivity of the catalyst system toward adventitious moisture. Whereas reactions run in “wet” PhCl enable formation of 3a in 87% yield (Table 1, entry 6), use of anhydrous PhCl as solvent resulted in a 58% yield of 3a (not shown). A sample of both “wet” and anhydrous PhCl were subjected to Karl-Fischer titration, revealing “anhydrous” PhCl contained 61.1 ppm water, whereas wet PhCl contained 138 ppm water. Deliberate use of water as an additive or cosolvent, however, led to low isolated yields of 3a. We speculate that adventitious water solubilizes K2CO3, but excess moisture may lead to formation of hydroxy-bridged rhodium dimers, which were demonstrated to be catalytically inactive.

Table 1.

Selected optimization experiments in the tandem rhodium-catalyzed transfer hydrogenative coupling-redox isomerization of alcohol 1a with butadiene 2a.a

graphic file with name nihms-1767391-t0002.jpg
Entry Catalyst K2CO3 (mol%) Solvent Yield (%)
➡ 1 Rh(acac)(CO)2 20 mol% PhCl 13
2 [Rh(cod)Cl]2 20 mol% PhCl 29
3 [Rh(CO)2Cl]2 20 mol% PhCl 53
4 Rh(cod)2OTf 20 mol% PhCl 65
5 Rh(cod)2BAr4F 20 mol% PhCl 70
6 Rh(cod)2BAr4F 50 mol% PhCl 87
7 Rh(cod)2BAr4F --- PhCl 29
8 Rh(cod)2BAr4F 50 mol% PhMe 71
9 Rh(cod)2BAr4F 50 mol% m-Xylene 55
10 Rh(cod)2BAr4F 50 mol% CF3-toluene 36
11 Rh(cod)2BAr4F 50 mol% Dioxane 43
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a

Yields are of material isolated by silica gel chromatography. The loading of dimeric rhodium pre-catalysts was 2.5 mol%. See Supporting Information for experimental details.

To evaluate reaction scope, optimal conditions for the conversion of 1a to branched ketone 3a were applied to diverse benzylic alcohols 1a–1r (Scheme 1). Transfer hydrogenative carbonyl addition-redox isomerization to form adducts containing electronically diverse aromatic (3a–3l) and heteroaromatic (3m–3r) rings occurred efficiently. This includes compounds containing furan (3m), benzothiophene (3n), indole (3o), pyridine (3q), and pyrimidine (3r) substructures. Application of these conditions to aliphatic alcohols led to low isolated yields of the corresponding ketones. Following additional optimization (see Supporting Information for details), it was found that the catalyst assembled in situ from Rh(cod)2OTf (7.5 mol%) and P(p-F-Ph)3 (18 mol%) delivered 3s in 75% yield. These conditions enabled conversion of aliphatic alcohols 1t–1x to branched ketones 3t–3x in good isolated yields. Under the present conditions, butadiene is a superior partner for C-C coupling. As illustrated by the conversion of alcohol 1a with isoprene 2b to deliver sec-isoamyl ketone 4a (eq. 1), the coupling of higher dienes is possible. However, attempted reactions of more complex dienes (myrcene, 2-phenylbutadiene, 1,3-cyclohexadiene, 1,3-pentadiene) using this first-generation catalytic system resulted in low conversion to the targeted ketone products (10-15% yield).

Scheme 1.

Scheme 1.

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Rhodium-catalyzed tandem transfer hydrogenative coupling-redox isomerization of primary alcohols 1a-1x with butadiene 2a to form isobutyl ketones 3a-3x.a

aYields are of material isolated by silica gel chromatography. See Supporting Information for experimental details. bConditions A: alcohol (100 mol%), butadiene (500 mol%), Rh(cod)2BAr4F (5 mol%), PPh3 (11 mol%), K2CO3 (50 mol%), PhCl (0.2 M), 130 °C. cConditions B: alcohol (100 mol%), butadiene (500 mol%), Rh(cod)2OTf (7.5 mol%), P(p-F-Ph)3 (18 mol%), K2CO3 (70 mol%), PhCl (0.2 M), 130 °C. dButadiene (800 mol%). eK2CO3 (30 mol%). fK2CO3 (70 mol%). gK2CO3 (90 mol%). hRh(cod)2OTf (10 mol%), P(p-F-Ph)3 (24 mol%).

graphic file with name nihms-1767391-f0004.jpg (eq. 1)

Whereas reactions that convert primary alcohols 1a-1x to isobutyl ketones 3a-3x are redox-neutral processes involving hydrogen auto-transfer, the conversion of aldehyde reactants to isobutyl ketones would represent a reductive process. As documented in the review literature,1i only a single method for rhodium-catalyzed reductive coupling of acyclic dienes with unactivated aldehydes has been reported, which utilizes Et3B (a pyrophoric liquid) as reductant.20 The development of a diene-aldehyde reductive coupling-redox isomerization mediated by abundant feedstock reductants (H2, 2-PrOH, NaO2CH) would be more desirable.2 To our delight, it was found that exposure of aldehydes dehydro-1a, dehydro-1g and dehydro-1s to butadiene 2a under standard conditions in the presence of sodium formate (500 mol%) enabled formation of the corresponding isobutyl ketones 3a, 3g and 3s in good yield (Scheme 2).

Scheme 2.

Scheme 2.

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Rhodium-catalyzed tandem formate-mediated reductive coupling-redox isomerization of aldehydes dehydro-1a, dehydro-1g and dehydro-1s with butadiene 2a to form isobutyl ketones 3a, 3g and 3s.a

aYields are of material isolated by silica gel chromatography. See Supporting Information for experimental details

To gain insight into the catalytic mechanism, deuterium labelling experiments were performed (Scheme 3). Exposure of d2-3-methoxybenzyl alcohol, deuterio-1a, to standard reaction conditions provides the isobutyl ketone deuterio-3a. Deuterium was transferred to the β-carbon (20% 2H at Hβ), the γ-carbon (95% 2H at Hγ), and the α-methyl carbon (27% 2H at HMe). Deuterium was not observed at the α-carbon (0% 2H at Hα). As branched homoallylic alcohols are putative intermediates in the formation of the isobutyl ketones 3a-3x, iso-deuterio-3a was subjected to standard reaction conditions in the absence of butadiene (to mitigate deuterium loss). The anticipated isobutyl ketone deuterio-3a′ was obtained, which incorporates deuterium at the β-carbon (43% 2H at Hβ), the γ-carbon (10% 2H at Hγ), the α-methyl carbon (42% 2H at HMe), but not at the α-carbon (0% 2H at Hα). The absence of deuterium at the α-carbon is due to protonation of a transient rhodium(I) enolate (that arises via hydrometalation of an intermediate enone) by primary alcohol reactant or secondary alcohol product. Whereas 71% total deuterium transfer was observed in the initial deuterium labelling experiment, 95% total deuterium transfer was observed in the latter experiment, which is conducted in the absence of butadiene. Indeed, it was found that the extent deuterium transfer was dependent upon the loading of butadiene (not shown). Finally, a double-labelling crossover experiment was conducted in which the homoallylic alcohols iso-deuterio-3a and iso-3i were exposed to standard reaction conditions in the absence of butadiene. Crossover of deuterium or hydrogen into the resulting ketones deuterio-3a′′ and 3i′ is not observed. The collective data suggest that both formation of the allylrhodium intermediate from butadiene and internal redox isomerization17,18 occur via rapid, reversible and non-regioselective hydrometalation events, and that the kinetic rhodium alkoxide enacts redox-isomerization without dissociation of rhodium at any intervening stage.

Scheme 3.

Scheme 3.

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Deuterium-labelling studies and double-labelling crossover experiment.a

aThe structural assignment of all deuterated compounds are based on 1H NMR, 2H NMR and HRMS analyses. 100% 2H refers to incorporation of a single deuterium atom at the indicated position. See Supporting Information for experimental details.

A general catalytic mechanism consistent with the results of deuterium labelling has been proposed (Scheme 4). Entry into the catalytic cycle via formation of a rhodium(I) alkoxide is followed by β-hydride elimination to generate an aldehyde and a rhodium(I) hydride. Hydrorhodation of butadiene delivers a nucleophilic allylrhodium(I) species that participates in aldehyde addition to form a branched homoallylic rhodium(I) alkoxide. This homoallylic rhodium(I) alkoxide affects redox isomerization17,18 through a series of β-hydride elimination hydrorhodation events to provide a rhodium enolate, which upon exchange with reactant alcohol releases the isobutyl ketone and regenerates the primary rhodium(I) alkoxide to close the catalytic cycle. As established by the double-labelling crossover experiment (Scheme 3), dissociation of rhodium does not occur at any stage during the course of redox isomerization.

Scheme 4.

Scheme 4.

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General catalytic mechanism for transfer hydrogenative carbonyl addition. As corroborated by deuterium labelling studies, dissociation of rhodium does not occur at any stage of the redox isomerization event.

In summary, we report the first examples of rhodium-catalyzed carbonyl addition via hydrogen auto-transfer, as illustrated in tandem carbonyl addition-redox isomerizations that directly convert primary alcohols and butadiene to isobutyl ketones. Additionally, related aldehyde-butadiene reductive couplings to form isobutyl ketones are achieved using formate as the terminal hydrogen source. These studies contribute to a growing class of atom-efficient processes that convert abundant chemical feedstocks to value added products in the absence of premetalated reagents or metallic reductants.2,21

Supplementary Material

Supporting Info

Acknowledgments.

The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445) are acknowledged for partial support of this research.

Footnotes

Supporting Information Available: Experimental procedures and spectral data. This material is available free of charge via the internet at http://pubs.acs.org.

The authors declare no competing financial interest.

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