DOI: 10.1002/chem.201405207

Communication

& Asymmetric Catalysis

Ruthenium-Catalyzed Tandem-Isomerization/Asymmetric Transfer Hydrogenation of Allylic Alcohols Tove Slagbrand, Helena Lundberg, and Hans Adolfsson*[a] plosive molecular hydrogen or moisture-sensitive hydride reagents.[18–20] Asymmetric transfer hydrogenation (ATH) of prochiral ketones provides enantiomerically enriched products under relatively environmentally friendly conditions.[21–25] Over the last decade, we have studied and developed catalysts based on ruthenium- and rhodium-arene complexes combined with simple a-amino acid ligands for this transformation. One of the most successful catalysts is formed in situ from the amino acid hydroxyamide ligand 1 (Figure 1 a), and [{Ru(p-cym-

Abstract: A one-pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem-isomerization/ asymmetric transfer hydrogenation process is efficiently catalyzed by [{Ru(p-cymene)Cl2}2] in combination with the a-amino acid hydroxyamide ligand 1, and performed under mild conditions in a mixture of ethanol and THF. The saturated alcohol products are isolated in good to excellent chemical yields and in enantiomeric excess up to 93 %.

The chemical industry and chemists in academia are constantly in need of simple preparative routes that provide complex molecules in few reaction steps. Therefore, the search for and optimization of new synthetic pathways, which allow for short reaction routes, is of high importance. It is beneficial if such synthetic procedures contain steps that can be combined in a sequential manner, called tandem or cascade reactions, which makes it possible to use unstable intermediates, produce less waste, use less solvent, and allow for faster formation of the desired product.[1] Here, we present a catalytic cascade protocol, which allows for the formation of enantiomerically enriched secondary alcohols by initial isomerization of racemic allylic alcohols, followed by reduction of the resulting ketones. There are several protocols available for the catalytic isomerization of allylic alcohols into aldehydes and ketones. The most common catalysts are based on late transition metals such as iridium, rhodium, ruthenium, and palladium.[2–10] The dimeric ruthenium complex, [{Ru(p-cymene)Cl2}2] is commonly employed as an isomerization catalyst, either on its own or in combination with different ligands and bases. Furthermore, several asymmetric isomerization protocols for the generation of enantiomerically enriched aldehydes and ketones have been developed, in which the stereogenic centers are in close proximity to the newly formed carbonyl functionality.[11–17] Transfer hydrogenations of unsaturated compounds are operationally simple and safe alternatives to reductions using ex-

Figure 1. a) The amino acid hydroxyamide ligand (1) (Boc = tert-butyloxycarbonyl). b) The proposed 6-membered transition state for the ATH.

ene)Cl2}2] in the presence of base.[26–30] The ATH of aryl alkyl ketones in 2-propanol was positively influenced by the addition of catalytic amounts of lithium chloride, and mechanistic investigations strongly support a hydride transfer via the bimetallic 6-membered transition state shown in Figure 1 b.[31, 32] The combination of the isomerization of allylic alcohols with a consecutive ketone reduction would allow for the formation of saturated alcohols in a straightforward manner as depicted in Scheme 1. The same type of compounds can, in principle, be reached by direct hydrogenation of the allylic alcohol; however, the sensitivity of the substrate being both allylic and ben-

[a] T. Slagbrand, H. Lundberg, Prof. Dr. H. Adolfsson Dept. of Organic Chemistry Stockholm University The Arrhenius Laboratory 10691 Stockholm (Sweden) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405207. Chem. Eur. J. 2014, 20, 1 – 6

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Scheme 1. A one-step procedure to obtain saturated alcohols from allylic alcohols that would otherwise require three or possibly two separate steps.

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Communication zylic would often lead to a nonselective reaction.[33, 34] The Cadierno group has demonstrated that racemic saturated alcohols can be obtained in a two-step reaction sequence, starting with isomerization of the allylic alcohol and, after isolation of the formed ketone, a subsequent reduction leading to the target compound.[35–38] Similarly, a two-step protocol for the formation of racemic alcohols by initial isomerization of nonaromatic allylic alcohols, followed by ketone reduction under transfer hydrogenation conditions was presented by Lau et al.[39] Employing the Noyori catalyst, [Ru(p-cymene)TsDPEN] (DPEN = 1,2-diphenyl-1,2-diaminoethane), Williams and coworkers showed that an allylic alcohol could be directly converted into the desired saturated alcohol with a conversion of 58 %, however, with an ee of 7 %.[40] Furthermore, Sowa demonstrated that the allylic alcohol moieties of simple isoprenoid alcohols were converted to the corresponding saturated alcohols in moderate to excellent enantioselectivity by a combined isomerization/reduction sequence catalyzed by [{Ru(p-cymene)Cl2}2] in the presence of (S)-tol-binap (tol-binap = 2,2’-bis(di-ptolylphosphino)-1,1’-binaphthyl). This particular transformation is an example of an asymmetric isomerization, which is followed by a transfer hydrogenation of the resulting aldehyde.[41] Encouraged by the high efficiency and selectivity in ATH reactions of aryl alkyl ketones demonstrated by the rutheniumcatalyst shown in Figure 1, we were interested in examining this particular catalyst in a combined isomerization/reduction sequence of allylic alcohols (Scheme 1). In an initial experimental setup, we used conditions developed for the reduction of acetophenones and applied these on the allylic alcohol 2 a (Scheme 2). Under these conditions, no sign of the desired product was observed; nevertheless, the expected ketone in-

Table 1. Optimization of solvent.[a]

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Conversion [%]

1 2 3 4 5 6 7 8 9 10 11

THF toluene 2-propanol:THF (1:1) 1-propanol:THF (1:1) ethanol:THF (1:1) ethanol:THF (3:1) ethanol:THF (1:3) ethanol:2-methyl THF (3:1) ethanol:toluene (1:1) ethanol:toluene (3:1) ethanol:toluene (1:3)

95[b] > 99 50 24 83 > 99 84 > 99 > 99 > 99 > 99

Alcohol ee 2 b [%] [%]

Ketone intermediate 2 c [%]

0 50 14 81 > 99 82 > 99 > 99 > 99 98

> 99 – 10 2 – 2 – – – 2

– nd 93[d] 83[d] 89[c] 80[d] 90[c] 89[c] 89[c] 79[d]

enantiomeric excess (Table 1, entry 6). The use of 2-methyl-THF, in combination with ethanol, gave an equally good result (Table 1, entry 8). Since the isomerization step proceeded smoothly in toluene, we examined mixtures of ethanol and toluene as reaction media and comparably, as with THF, good results were obtained (Table 1, entries 9 and 10). However, THF was chosen as co-solvent in further studies, due to workup simplicity. The optimizations were continued by screening the amount of base (see the Supporting Information), and it was found that using potassium tert-butoxide (30 mol %) was optimal. In order to further improve the outcome of the reaction, additional reaction parameters such as concentration and the [Ru]/ ligand ratio were screened (Table 2). Control experiments were performed without the ligand, without ruthenium, and one

Table 2. Further optimization of reaction parameters.[a]

termediate (2 c) was detected. Changing the base to potassium tert-butoxide and increasing the amount to one equivalent, gratifyingly resulted in the formation of the desired product 2 b (Table 1, entry 3). Further optimizations included evaluation of different solvents and hydride sources. As shown in Table 1, isomerization can occur in the absence of a hydride source (Table 1, entries 1 and 2). In order to get the saturated asymmetric alcohol, a hydride source is required and, therefore, we examined a number of simple alkyl alcohols in combination with THF as co-solvent (Table 1, entries 3–5). Performing the reaction in a 1:1 mixture of ethanol and THF led to an acceptable yield of alcohol 2 b (Table 1, entry 5), and increasing the amount of ethanol gave the saturated alcohol as the sole product in good &

Solvent (ratio)

[a] Reaction conditions; [{Ru(p-cymene)Cl2}2] (2 mol %, 4 mol % ruthenium), ligand 1 (8.8 mol %), allylic alcohol 2 a (0.5 mmol, 0.5 m reaction solution), LiCl (10 mol %), dry THF/toluene/ethanol/1-propanol/2-propanol, potassium tert-butoxide (0.5 mmol), 40 8C, reaction time 3 h. Conversion was determined using 1H NMR spectroscopy. [b] A complex mixture of products was obtained. [c] The ee was measured with chiral GLC (CP Chirasil DEX CB). [d] The ee was measured with HPLC (OB column).

Scheme 2. Starting point for the optimization based on the reduction of acetophenones, which only gave the isomerized product.

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Entry

Ru Ligand Allylic Ketone Conv- Alcohol ee [mol %] [mol %] alcohol ersion 2 b [%] [%][b] intermediate [M] 2 c [%] [%]

1 2 3 4 5 6 7 8 9

4 4 – 4 4 4 4 2

8.8 – 8.8 – 8.8 8.8 4.4 2.2 1.1

0.5 0.5 0.5 0.5 0.1 0.05 0.5 0.5 0.5

> 99 92 0 0 82 62 > 99 > 99 > 99

> 99 – – – 63 29 91 > 99 95

92 – – – 91 84 92 93 92

– 92 – – 19 33 9 – 5

[a] Reaction conditions: Allylic alcohol 2 a (0.5 mmol, 0.5 m reaction solution), LiCl (10 mol %), dry ethanol:dry THF (3:1), potassium tert-butoxide as base (30 mol %), temperature 40 8C, reaction time 3 h. Conversion was determined using 1H NMR spectroscopy. [b] The ee was measured with chiral GLC (CP Chirasil DEX CB).

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Communication with neither of the two species Table 3. Substrate scope.[a] (Table 2, entries 2–4). The reacEntry Substrate Product Conversion [%] Isolated ee [%][b] Absolute tion did not proceed in the abyield [%] config.[c] sence of the ruthenium complex, as would be expected (Table 2, 1 2a 2b > 99 85 93 S entries 3 and 4). However, it was found that isomerization was taking place even without ligand 2 3a 3b > 99 91 88 S present, resulting in 92 % conversion of the allylic alcohol into the ketone (Table 2, entry 2). This 3 4a 4b > 99[d] 83 82 S result clearly shows that the ligand is crucial for the reduction of the ketone, whereas it may or 4 5a 5b > 99 94 89 S may not play a role for the isomerization process. Ongoing mechanistic studies will answer 5[e] 6a 6b > 99 95 84 S this question in due time. The reaction concentration was also evaluated (Table 2, entries 5 and 6 7a 7b > 99[f] 53 84 S 6), showing that lower concentration results in a slower reac7 8a 8b > 99 86 – – tion. Since the isomerization can occur without the ligand present 8[g] 9a 9b > 99 97 22 R (Table 2, entry 2), the [Ru]:ligand ratio was changed (Table 2, en10 b > 99 97 11 R 9 10 a tries 7 and 8). With almost equimolar amounts of the ruthenium 10 11 a 11 b > 99 91 61 S precursor and ligand, there was still some ketone left in the reaction mixture after 3 h reaction 12 b > 99[h] 63 74 S 11 12 a time (Table 2, entry 7). However, with the metal precursor in [a] Reaction conditions: [{Ru(p-cymene)Cl2}2] (1 mol %), ligand 1 (1.1 mol %), allylic alcohol (1 mmol, 0.5 m reaction solution), LiCl (10 mol %), dry ethanol and dry THF (3:1) as solvent, potassium tert-butoxide as base excess, the reaction went to (30 mol %), 40 8C, reacted 16–24 h. Conversion was determined using 1H NMR spectroscopy. [b] The ee was completion (Table 2, entry 8) measured with chiral GLC (CP Chirasil DEX CB). [c] Absolute configuration was determined by optical rotation. and, gratifyingly, the catalyst [d] Ketone (6 %). [e] Reaction time 10 h. [f] For product distribution, see Scheme 3. [g] Reaction time 5 h. loading could now be decreased [h] Ketone (25%). to 2 mol % without dramatically changing the outcome (Table 2, entry 9). Further decrease in catalyst loading resulted in incomplete reaction, along with a significant amount of ketone (20 %) left in the reaction mixture after 3 h reaction time. Scheme 3. The product distribution for the naphthyl allylic alcohol (7 a). With the optimized conditions in hand we focused on evaluating the tandem isomerization/ the ketone, which reacted with acetaldehyde formed from oxiATH on a series of different racemic allylic alcohols (Table 3). dized ethanol. The protocol works well for allylic alcohols substituted with The primary allylic alcohol 8 a was efficiently converted into electron-withdrawing or electron-releasing substituents on the the saturated product (Table 3, entry 7). Furthermore, the isoaryl moiety (Table 3, entries 2–5), yielding products with ee in merization/reduction reaction was successfully performed on the range of 82–89 %. Interestingly, the naphthyl derivative 7 a the secondary allylic alcohols 9 a and 10 a (Table 3, entries 8 gave rise to a mixture of different compounds, of which alcoand 9). In the latter two entries, low enantiomeric excess of hol 7 b was the major product, along with the ketone 7 c, and the formed secondary-saturated alcohols were obtained, which the alkylated ketone 7 d (Table 3, entry 6, and Scheme 3). is in line with previous results from performing ATH on subKetone 7 d is the condensation product from the enolate of Chem. Eur. J. 2014, 20, 1 – 6

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Communication strates that lack an aromatic moiety next to the ketone. The heteroaromatic allylic alcohols 11 a and 12 a were also examined, and we found that these compounds were efficiently converted to the corresponding saturated alcohols, albeit with slightly lower ee (Table 3, entries 10 and 11). In addition to the allylic alcohols presented in Table 3, the isomerization/reduction sequence was performed on compounds 13 a–15 a (see Scheme 4). Poor conversion was obtained running the reaction on allylic alcohol 13 a, which can

substrate behaves in a similar way to the intermediate formed from the allylic alcohol under these conditions. To conclude, we have developed an efficient protocol for the ruthenium-catalyzed tandem isomerization/asymmetric transfer hydrogenation of allylic alcohols into the corresponding saturated alcohols. The methodology provides enantiomerically enriched saturated alcohols in up to 93 % ee, from simple racemic allylic alcohols under relatively mild reaction conditions. The protocol is complementary to previously published methods, being applicable to secondary as well as primary allylic alcohols. The one-pot reaction setup allows for the direct formation of chiral target alcohols without the need for isolation and purification of intermediates.

Experimental Section

Scheme 4. Poorly reactive substrates.

All reactions were performed under nitrogen with oven-dried glassware.

be explained by increasing steric hindrance next to the intermediate ketone, a situation that severely hampers the final reduction step. The isomerization/reduction did not work at all on compounds 14 a and 15 a. The lack of reactivity of 14 a can be explained by steric hindrance that prevents the isomerization from occurring, whereas in allylic alcohol 15 a there is a possible inhibition of the reaction due to coordination of the nitro moiety to the ruthenium center. The latter has been observed previously in attempts to reduce nitro-substituted acetophenones under transfer hydrogenation conditions with this class of catalysts. The mechanisms of the individual reaction steps in the ruthenium-catalyzed tandem isomerization/ATH process have been carefully studied.[42, 43] For the isomerization of allylic alcohols into the corresponding aldehydes/ketones, there are several different mechanistic possibilities, in which the transition metal center of the catalyst can either interact with the olefinic or the hydroxyl functionality of the substrate. It has been proposed in the literature that the isomerization can proceed via an a,b-unsaturated ketone intermediate, as depicted in Scheme 1.[44, 45] Therefore, we investigated whether ketone 16 could be an intermediate of the process by using this compound as substrate to see whether the fully reduced alcohol would be formed (Scheme 5). Performing the reaction under optimized conditions, compound 16 was converted to the target alcohol 2 b. The saturated alcohol was formed in 91 % ee, hence, approximately the same selectivity as starting with allylic alcohol 2 a. This result indicates that ketone 16 could be an intermediate in the isomerization mechanism, or that this

General procedure for the tandem isomerization/asymmetric transfer hydrogenation of allylic alcohols: The catalyst precursor [{Ru(p-cymene)Cl2}2] (6.2 mg, 0.01 mmol) and LiCl (4.4 mg, 0.10 mmol, 10 mol %) were treated under vacuum in a microwave vial for 10 min. Dry THF (0.50 mL) and dry ethanol (1.10 mL) were added, followed by a 0.11 m stock solution of ligand 1 in dry ethanol (0.10 mL, 0.011 mmol, 1.1 mol %) and the allylic alcohol (1.0 mmol), and the resulting mixture was stirred for 15 min at 40 8C. The reaction was initiated by addition of a 1.0 m stock solution of KtBuO in dry ethanol (0.30 mL, 0.30 mmol, 30 mol %). Aliquots were withdrawn at suitable intervals (see details in the tables) and were then pressed though a pad of silica with ethyl acetate as the eluent. The resulting solutions were analyzed by 1 H NMR spectroscopy, chiral GLC (CP Chirasil DEX CB) or chiral HPLC (OB column).

Acknowledgements The Swedish Research Council, the Knut and Alice Wallenberg Foundation, and Stockholm University are gratefully acknowledged for financial support. Keywords: allylic alcohols · asymmetric isomerization · reduction · ruthenium

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[1] V. M. Lombardo, C. D. Thomas, K. A. Scheidt, Angew. Chem. 2013, 125, 13148 – 13152; Angew. Chem. Int. Ed. 2013, 52, 12910 – 12914. [2] J.-E. Bckvall, U. Andreasson, Tetrahedron Lett. 1993, 34, 5459 – 5462. [3] L. Mantilli, C. Mazet, Tetrahedron Lett. 2009, 50, 4141 – 4144. [4] R. C. van der Drift, M. Vailati, E. Bouwman, E. Drent, J. Mol. Catal. A 2000, 159, 163 – 177. [5] V. Cadierno, P. Crochet, J. Gimeno, Synlett 2008, 8, 1105 – 1124. [6] P. Crochet, J. Des, M. A. Fernndez-Zfflmel, J. Gimeno, Adv. Synth. Catal. 2006, 348, 93 – 100. [7] P. Crochet, M. A. Fernndez-Zfflmel, J. Gimeno, M. Scheele, Organometallics 2006, 25, 4846 – 4849. [8] R. C. van der Drift, M. Gagliardo, H. Kooijman, A. L. Spek, E. Bouwman, E. Drent, J. Organomet. Chem. 2005, 690, 1044 – 1055. [9] A. J. S. Johnston, M. G. McLaughlin, J. P. Reid, M. J. Cook, Org. Biomol. Chem. 2013, 11, 7662 – 7666. [10] R. Uma, C. Crvisy, R. Gre, Chem. Rev. 2003, 103, 27 – 51. [11] K. Tanaka, G. C. Fu, J. Org. Chem. 2001, 66, 8177 – 8186.

Scheme 5. Reduction of ketone 16 using the optimized conditions for the tandem isomerization/ATH process.

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Received: September 10, 2014 Published online on && &&, 0000

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COMMUNICATION & Asymmetric Catalysis T. Slagbrand, H. Lundberg, H. Adolfsson* && – && Ruthenium-Catalyzed TandemIsomerization/Asymmetric Transfer Hydrogenation of Allylic Alcohols

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Less is more: The combination of [{Ru(p-cymene)Cl2}2] with an amino acid hydroxyamide ligand allows for the direct catalytic tandem-isomerization/ asymmetric transfer hydrogenation of racemic allylic alcohols to saturated

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enantiomerically enriched alcohols. A series of racemic allylic alcohols are converted into saturated alcohols under mild reaction conditions in a mixture of ethanol and THF (see scheme).

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asymmetric transfer hydrogenation of allylic alcohols.

A one-pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem-iso...
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