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Published in final edited form as: Org Lett. 2019 Jul 22;21(16):6447–6451. doi: 10.1021/acs.orglett.9b02342

Base-Mediated Meerwein–Ponndorf–Verley Reduction of Aromatic and Heterocyclic Ketones

Timothy B Boit 1, Milauni M Mehta 1, Neil K Garg 1,*
PMCID: PMC7193670  NIHMSID: NIHMS1580875  PMID: 31329452

Abstract

An experimental protocol to achieve the Meerwein–Ponndorf–Verley (MPV) reduction of ketones under mildly basic conditions is reported. The transformation is tolerant of a range of ketone substrates, including O- and S-containing heterocycles, is scalable, and shows potential to be used as a platform to access enantioenriched products. These studies provide a general method for achieving the reduction of ketones under mildly basic conditions and offer an alternative protocol to more well-known Al-based MPV reduction conditions.

Graphical Abstract

Graphical abstract

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The Meerwein–Ponndorf–Verley (MPV) reaction is an important and powerful tool for the reduction of ketones and aldehydes because of its chemoselectivity, mild reaction conditions, scalability, and low operational cost.1 Discovered nearly a century ago,2 the traditional MPV reduction employs an aluminum alkoxide catalyst generated from a secondary alcohol (most commonly isopropanol) to achieve the reversible transfer hydrogenation of carbonyl substrates (Figure 1).3 This venerable reaction has been featured in the syntheses of several natural products4 and spurred numerous experimental5 and computational studies.6 Despite the synthetic utility of the traditional MPV reduction, several drawbacks exist. These include long reaction times, the need for a large excess of reducing agent, competing side reactions such as aldol condensation and the Tishchenko reduction of aldehydes, and low enantioselectivities in the case of intermolecular asymmetric variants.1,3 Methodological advances to address these limitations include the use of additives,7 microwave irradiation,8 and the development of novel aluminum,9 organoboron,10 and metal alkoxide catalysts (i.e., transition11 and lanthanide12). A particularly efficient aluminum siloxide catalyst has been reported by the Krempner group.9c

Figure 1.

Figure 1.

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Traditional MPV reduction of ketones and base-mediated variant (prior studies).

A largely unexplored approach to the MPV-type reduction of carbonyls uses simple alkali metal alkoxides (Figure 1).13,14 This variant of the MPV reaction has several benefits including its avoidance of transition and main group metal catalysts, operational simplicity, and compatibility with heteroatoms known to inhibit metal catalysis.3,13 Specifically, isopropoxide catalysts generated from strong alkali bases, such as NaOH13a and KOH13b and milder bases such as K3PO4,13c have been employed in the reduction of aldehydes and ketones. Nevertheless, a number of limitations of the base-mediated MPV reduction remain unaddressed including a limited scope and the reliance on i-PrOH as the solvent and hydride source.15 Additionally, no examples of stereoselective base-mediated MPV reactions exist. We report the use of a simple potassium alkoxide reductant, generated in situ from the corresponding alcohol and K3PO4, for the reduction of a wide range of aromatic ketones. This methodology is tolerant of heterocycles, is scalable, and shows potential for the asymmetric reduction of alkyl–aryl ketones.

To initiate our studies, we examined the reduction of dihydrochalcone (1) using alkyl–alkyl secondary alcohols and K3PO4, a readily available and mild base (Table 1).16 Subjecting 1 to catalytic K3PO4 using isopropanol or 3-pentanol (3, 2.5 equiv) in 1,4-dioxane at 80 °C provided none of the desired alcohol product 2 (entries 1 and 2).16–18 Owing to the potential reversibility of the reaction,1a–c,16 we turned to the use of aryl–alkyl reductants to bias the reaction equilibrium. Importantly, this class of alcohols enabled greater control of the redox properties of the reductant. We evaluated alcohol 4 and the more electron-rich derivative 5 as reductants,19 anticipating that the stability of the respective aryl ketone and doubly vinylogous amide byproducts would drive the forward reaction to yield 2. Gratifyingly, the use of 2.5 equiv of 4 or 5 provided 2 in 40% and 61% yield, respectively (entries 3 and 4). Employing reductant 5 at 120 °C furnished desired product 2 in 92% yield (entry 5). Finally, alcohol 2 was obtained in near-quantitative yield by utilizing excess base (entry 6).

Table 1.

Optimization of Reaction Conditions

graphic file with name nihms-1580875-t0002.jpg
entry reductant equiv K3PO4 temp (°C) yield
1 i-PrOH 0.50 80 0%
2 3 0.50 80 0%
3 4 0.50 80 40%
4 5 0.50 80 61%
5 5 0.50 120 92%
6 5 4.0 120 99%
graphic file with name nihms-1580875-t0003.jpg
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a

General conditions unless otherwise stated: substrate 1 (1.0 equiv, 0.10 mmol), K3PO4 (0.50–4.0 equiv), reductant (2.5 equiv), and 1,4-dioxane (1.0 M) heated at 80–120 °C for 16 h in a sealed vial under an atmosphere of N2. Yields determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an external standard.

With optimized conditions in hand, we examined a range of aryl ketone substrates in the reduction (Figure 2). Linear and α-branched substrates smoothly underwent reduction, giving rise to alcohols 2 and 6–8 in good yields. Of note, steric bulk on the alkyl substituent of the ketone was tolerated, as shown by the successful reduction of tert-butyl phenyl ketone to furnish alcohol 8 in 83% yield. The reduction of α-tetralone to give α-tetralol (9) in 86% yield demonstrates competence of a cyclic ketone substrate in this transformation. Notably, we found that electron-rich aromatic ketones and those highly decorated with heteroatom substituents underwent facile reduction, as demonstrated by the formation of alcohols 10 and 11 in 81% and 87% yield, respectively. Finally, both electron-rich and electron-deficient benzophenone derivatives were suitable substrates, as shown by the production of alcohol products 12 and 13 in good yields.

Figure 2.

Figure 2.

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Scope of the base-mediated MPV reduction of aromatic ketones. Conditions: substrate (1.0 equiv, 0.10 mmol), K3PO4 (4.0 equiv), reductant (2.5 equiv), and 1,4-dioxane (1.0 M) heated at 120 °C for 16 h in a sealed vial under an atmosphere of N2. Unless otherwise noted, yields reflect the average of two isolation experiments. a Yield determined by 1H NMR analysis using hexamethylbenzene as an external standard. b Reaction heated at 80 °C for 16 h.

We next set out to evaluate the reactivity of a number of heterocyclic ketone substrates, as only a few examples of base-mediated MPV reductions of heterocyclic ketones have been previously reported (Figure 3).20 Benzofuran- and dibenzofuran-containing ketones underwent reduction to provide alcohols 14 and 15 in 73% and 76% yield, respectively. Benzodioxole and benzodioxane moieties were also well tolerated, as seen by the formation of alcohols 16 and 17 in good yields. Lastly, ketones bearing thiophenes were successfully employed, as judged by the formation of benzothiophene 18 and tetrahydrobenzothiophene 19 in 70% and 73% yield, respectively.21

Figure 3.

Figure 3.

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Scope of the base-mediated MPV reduction of heteroaromatic ketones. Conditions: substrate (1.0 equiv, 0.10 mmol), K3PO4 (4.0 equiv), reductant (2.5 equiv), and 1,4-dioxane (1.0 M) heated at 120 °C for 16 h in a sealed vial under an atmosphere of N2. Unless otherwise noted, yields reflect the average of two isolation experiments. a Yield determined by 1H NMR analysis using hexamethylbenzene as an external standard. b Reaction heated at 130 °C for 16 h.

As a demonstration of the utility of the base-mediated MPV reduction of ketones, we performed the additional studies shown in Figure 4. In the first, we performed a gram-scale reduction of acetyldibenzofuran 20.22 Carrying out the reaction at 130 °C for 24 h delivered alcohol 15 in 66% yield, thus demonstrating the scalability of this methodology. Next, we questioned whether this reaction could be used for the synthesis of enantioenriched alcohols. Toward this end, we performed the reduction of phenylcyclohexyl ketone 21 using enantioenriched (R)-5. This proceeded to give alcohol (S)-6 with 50% stereochemical transfer (96% ee of (R)-5 → 48% ee (S)-6). This result underscores the potential of the base-mediated MPV reduction to generate enantioenriched products.1e,12d,23

Figure 4.

Figure 4.

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Gram-scale reduction and stereochemical transfer studies demonstrating the synthetic utility of the base-mediated MPV reduction. Conditions: substrate (1.0 equiv), K3PO4 (4.0 equiv), reductant (2.5 equiv), and 1,4-dioxane (1.0 M) heated at the indicated temperature and time in a sealed vial under an atmosphere of N2.

In summary, we have developed the base-mediated MPV reduction of aromatic and heteroaromatic ketones.24 This methodology employs the simple combination of K3PO4 as a mild base and secondary alcohol 5 as the reductant. The transformation is tolerant of a range of ketone substrates, including O- and S-containing heterocycles, and avoids the hydride source being used as the solvent. The reduction has been demonstrated on gram scale and shows potential to be used as a platform to provide enantioenriched products. These studies provide a general platform for achieving the reduction of ketones under mildly basic MPV conditions and offer an alternative protocol to the more classic Al-based MPV reduction. We hope this study will enable the greater utilization of the uncommon base-mediated variant of the MPV reduction in chemical synthesis.

Supplementary Material

supporting info

■ ACKNOWLEDGMENTS

The authors thank the NIH-NIGMS (R01-GM117016 to N.K.G.), the California Tobacco-Related Disease Research Program (28DT-0006 to T.B.B.), the Trueblood Family (N.K.G.), and the University of California, Los Angeles, for financial support. Colleen Hui (UCLA) is acknowledged for assistance in performing trace metal analysis. Dr. Junyong Kim is acknowledged for experimental assistance. We thank the Nelson laboratory (UCLA) for use of instrumentation. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631).

Footnotes

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02342.

Experimental details and compound characterization data (PDF)

The authors declare no competing financial interest.

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