Acceptorless ruthenium catalyzed dehydrogenation of alcohols to ketones and esters

Abstract

The ruthenium complex [RuCl₂(p-cymene)(IMes)] catalyses the dehydrogenation of alcohols in the presence of K₃PO₄ as a base and without a hydrogen acceptor. Secondary alcohols are converted to the corresponding ketones whereas primary alcohols are transformed into esters. The dehydrogenation protocol was successfully extended to the dehydrogenation of methyl ricinoleate, a renewable fatty acid methyl ester (FAME), furnishing in high yields the saturated keto-ester methyl 12-oxostearate via a hydrogen borrowing alcohol dehydrogenation–alkene hydrogenation tandem reaction.

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Introduction

Oxidation reactions have always played a pivotal role in chemistry allowing the synthesis of both base and fine chemicals.¹ The development of efficient and selective catalysts contributes to decreasing the environmental impact of oxidation by making possible the use of more environmentally acceptable oxidizing agents such as H₂O₂ or O₂ instead of hazardous and toxic stoichiometric reagents. In this regard, the catalytic dehydrogenation of alcohols² is a very appealing oxidant free process that is attracting interest for the synthesis of carbonyl compounds although it was originally studied for hydrogen production. In this domain the pioneering work by Dobson and Robinson³ and more recently the results obtained by Morton and Cole-Hamilton⁴ and Beller et al.⁵ on the ruthenium and rhodium catalyzed dehydrogenation of simple alcohols are good illustrations. The dehydrogenation of alcohols for the production of carbonyl compounds is more recent and has found very interesting extensions in tandem and hydrogen borrowing reactions.⁶ Several metals have shown good activity for promoting alcohol dehydrogenation of which those operating without assistance of an hydrogen acceptor are the most interesting from a synthetic point of view.⁷ In 2003, Hulshof et al. extended the use of the Robinson catalyst to the synthesis of ketones^7a and in 2005 Adair and Williams reported a catalytic system based on simple ruthenium complexes and triphenylphosphine allowing the synthesis of various ketones with high conversions.^7c In the meantime, Milstein et al. reported in 2004 ruthenium–pincer complexes operating at very low catalyst loading.^7b More recent examples confirmed the high activity of sophisticated ruthenium complexes bearing non-innocent pincer ligands.⁸ Surprisingly, despite their strong impact on many organometallic catalyzed reactions, N-Heterocyclic Carbenes (NHCs) that can now be easily installed on various transition metals allowing for a broad range of steric and electronic variations⁹ have been understudied in the field of dehydrogenation of alcohols. To the best of our knowledge metal–NHC catalysts have been used only in tandem reaction involving an initial dehydrogenation of alcohols.^6l–q Herein, we present our preliminary results on the dehydrogenation of alcohols using the ruthenium–NHC complex [RuCl₂(p-cymene)IMes],^10a–cA, that was previously used in catalytic transformations such as olefin metathesis¹⁰ and ATRP.¹¹ We show that this very easily prepared complex is more active than the previously reported phosphine based catalytic system by Williams as high conversions and yields can be reached using lower catalyst loading. The scope of this catalyst was extended to the dehydrogenation of primary and secondary alcohols. In particular, the oxidation of the renewable methyl ricinoleate arising from castor oil¹² was achieved.

Results and discussion

The dehydrogenation of methylphenylcarbinol 1 was used as a model reaction for the evaluation and optimization of experimental parameters (Scheme 1). For practical reasons and for better discrimination of the experimental parameters, we first performed our tests at 100 °C (oil bath) for 15 h. For efficient removal of the liberated hydrogen, the reactions were conducted in open systems connected to a flow of argon.

Scheme 1 Dehydrogenation of methylphenylcarbinol 1.

We initially tested several bases as it is well established in the literature that the nature of the base has a strong influence on the reaction efficacy and selectivity. Ideally, the base should be easy to handle and of low toxicity and cost. Thus, a series of inorganic and organic bases were evaluated for the dehydrogenation of 1. As depicted in Table 1, LiOH, Cs₂CO₃ and K₃PO₄ showed nearly similar results (Table 1, entries 1, 3, and 5). Organic bases failed to provide the desired product and KOH was very efficient for the production of the partially hydrogenated aldol product (Table 1, entry 6).¹³ Of note, LiOH·H₂O was not as effective as the 3 best inorganic bases,^7c and blank tests performed in the absence of a base (Table 1, entry 10) and metal (Table 1, entries 11 and 12) showed that both components are required to promote the reaction.

Table 1 Base screening for the dehydrogenation of 1^a

Entry	Base	Conversion^b (%)	Yield^c (%)
a 1 (0.8 mmol), A (5 mol%), base (15 mol%), toluene (2.0 mL), 100 °C, 15 h. b Determined by gas chromatography using dodecane as an internal standard. c Isolated yields. d Not determined. e Without catalyst A.
1	LiOH	47	45
2	LiOH·xH2O	37	30
3	Cs2CO3	50	39
4	K2CO3	40	22
5	K3PO4	48	37
6	KOH	98	22
7	KOAc	48	17
8	Et3N	38	13
9	N,N-DMEDA	Trace	n.d.^d
10	No base	0	0
11^e	LiOH	0	0
12^e	K3PO4	0	0

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The screening of various experimental parameters for improved efficiency was pursued with LiOH and K₃PO₄ as bases, Cs₂CO₃ being excluded for cost reasons. When a slight temperature increase to 110 °C was not found to significantly improve the reaction efficiency, an increase of substrate concentration resulted in better performances. Thus, reaction conducted at 110 °C with a [1] = 0.8 M resulted in conversions of 57% and 58%, and yields¹⁴ of 49% and 47% using K₃PO₄ and LiOH, respectively. Since no appreciable difference was observed between K₃PO₄ and LiOH, the latter was discarded on the basis of higher toxicity.¹⁵ With these experimental conditions in hands, the dehydrogenation of 1 was conducted over 48 h leading to the formation of 2 in a modest 55% isolated yield with 30 mol% of K₃PO₄. Further increase of the base content to 50% enabled full conversion of 1 and furnished 2 in 80% isolated yield (Table 2, entry 1). Next, the decrease of catalyst loading was investigated. As depicted in Table 2, when the catalyst loading was decreased to 2.5 mol% the conversion dropped to 70%. However, high conversion could be restored in refluxing toluene (125 °C, oil bath). Further decrease of the catalyst loading resulted in incomplete conversion even at 125 °C (Table 2, entry 4).

Table 2 Optimization of catalyst loading for the dehydrogenation of 1^a

Entry	A (mol%)	T/°C	Conversion (%)^b	Yield^c
a 1 (0.8 mmol), K3PO4 (50 mol%), toluene (1.0 mL), 48 h. b Determined by gas chromatography using dodecane as an internal standard. c Isolated yield.
1	5	110	100	80
2	2.5	110	70	58
3	2.5	125	97	78
4	2	125	78	n.d.

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With the optimum experimental conditions established we next investigated the scope of the reaction using various secondary and primary alcohols (Table 3).

Table 3 Dehydrogenation of secondary and primary alcohols catalysed by A^a

Entry	Alcohol	Conversion (%)	Yield^d (%)
a Alcohol (0.8 mmol), A (2.5 mol%), K3PO4 (50 mol%), toluene (1 mL), 125 °C, 48 h. b Determined by gas chromatography using dodecane as an internal standard. c Determined by ^1H NMR. d Isolated yields. e Isolated esters.
1		86^b	84
2		97^b	96
3		53^c	50
4		55^b	45
5		85^b	73
6		60^c	56
7		66^c	50^e
8		41^c	30^e

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The dehydrogenation of secondary benzylic alcohols proceeded with high conversions providing the desired ketones in high yields. The reaction tolerated the steric hindrance of an o-methyl substituent and was not sensitive to a p-OMe electron donating group whereas a p-CF₃ electron withdrawing substituent reduced the catalytic efficiency (entries 1–3). The sterically hindered and functionalised alcohol 6, a precursor of a propargylic alcohol used in the preparation of an olefin metathesis catalyst,¹⁶ was found to be reluctant to conventional MnO₂ oxidation, however when subjected to our dehydrogenation protocol, the corresponding ketone was obtained in 45% yield. O-Tetralol 7 which is often used as a model substrate in dehydrogenation reactions was also efficiently transformed with 85% conversion and the corresponding ketone was isolated in 73% yield (Table 3, entry 5). For comparison, this transformation proceeded with full conversion under Williams' conditions using 5 mol% of catalyst^7c and under Baratta's conditions using only 0.4 mol% of a [(diamino)-(diphenylphosphinoferrocene)–ruthenium(II)] complex in the presence of tBuOK as a base.^8b The dehydrogenation of 8, a secondary, less reactive “non-benzylic” alcohol, proceeded with lower efficacy furnishing the corresponding ketone in a modest 56% yield. The dehydrogenation of primary alcohols was next investigated using 1-octanol and benzyl alcohol as model substrates. Whereas the dehydrogenation of secondary alcohols readily leads to the corresponding ketones, the dehydrogenation of primary alcohols leading to aldehydes is rare^6h,7f and rather leads to the corresponding esters.^6k,q,8a When 1-octanol 9 and benzyl alcohol 10 were subjected to the dehydrogenation transformation catalysed by A, both reactions proceeded with low conversions furnishing the corresponding esters in moderate yields (entries 7 and 8).¹⁷ Renewable materials are receiving increasing interest as alternative raw material sources for the production of petrochemicals.¹⁸ In this context, methyl ricinoleate 11, a hydroxyl-containing fatty acid methyl ester (FAME), has found utility in polymer synthesis in particular for the production of polyamide monomers.¹⁹ FAME derivatives have also found many applications as polymer additives obtained by chemical modification of the carbon–carbon double bond.²⁰ Thus the search for new FAME derivatives as well as efficient and green transformation methods is of great importance. In this regard, the ketonization of FAMEs based on carbon–carbon double bond oxidations has attracted interest but was found to be hampered by regioselectivity issues leading to mixtures of ketones.²¹ For example, ketonization of methyl oleate leads in general to mixtures of methyl-C(9) and C(10)-oxostearate.

We envisioned that the dehydrogenation of methyl ricinoleate could be a straightforward and necessarily regioselective way to introduce a keto functionality on the fatty ester carbon chain.

Furthermore, it was also expected that the carbon–carbon double bond could serve as a hydrogen acceptor and be hydrogenated in a tandem alcohol dehydrogenation–alkene hydrogenation reaction. Methyl ricinoleate was thus subjected to the dehydrogenation procedure (see conditions in Table 3) and was quantitatively converted in 48 h. As anticipated we were pleased to obtain methyl 12-oxooctadecanoate 12 (methyl 12-ketostearate) as the only product of the reaction that was isolated in 90% yield (Scheme 2).²²

Scheme 2 Dehydrogenation of methyl-12-ricinoleate 11.

Conclusions

The catalytic activity of the simple RuCl₂(p-cymene)(IMes) complex in the dehydrogenation of alcohols was demonstrated. This oxidant free oxidation catalyst operates in the presence of a cheap and non-toxic base and does not require a hydrogen acceptor. Secondary alcohols were efficiently transformed into the corresponding ketones whereas primary alcohols lead to the formation of esters. We have shown in a selected example that this oxidation protocol could be used as an alternative to more conventional oxidation methods that failed to provide the desired ketone. The dehydrogenation protocol was also successfully applied to the dehydrogenation of the renewable methyl ricinoleate leading in high yield to the high value-added methyl 12-oxooctadecanoate. Although the catalytic activity of this complex is still below that of other catalysts based on more sophisticated pincer-type architectures, it compares favourably with other easily accessible ruthenium based catalysts. The diversity in structures and properties of NHCs and arene–ruthenium complexes will be further screened in order to improve the catalytic performances.

Acknowledgements

The authors thank the Agence Nationale de la Recherche for financial support (NanoRemCat2 ANR-09-CP2D-11-02) and for a grant to S.S.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cy20066j

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