Brønsted Acid Mediated Direct α-Hydroxylation of Cyclic α-Branched Ketones

Key words

α-branched ketones - α-hydroxylation - aminoxylation - α-functionalization of ketones - enolization - Brønsted acid mediated

The direct α-hydroxylation of carbonyl compounds represents an efficient approach towards α-hydroxy carbonyls, a ubiquitous motif in pharmaceuticals and natural products (Scheme [1, a]).[1] Although α-hydroxylations of linear aldehydes and ketones are well established, such reactions of their branched derivatives still remain a challenge.[2] α-Branched ketones are particularly difficult substrates because of the added challenge of controlling the branched vs. unbranched regioselectivity. It is therefore not surprising that a general solution does not exist and common synthetic strategies towards α-hydroxy carbonyls rely on the oxidation of prefunctionalized substrates, e.g., enol ethers and enol esters.[3] Few direct methods, which combine catalytic/substoichiometric amounts of (transition) metals, iodine, or strong bases with oxygen, DDQ, or DMSO as the corresponding oxidant, were recently reported (Scheme [1, b]).[4]

Scheme 1 (a) Natural products and pharmaceuticals containing the α-hydroxy ketone motif. (b) Previous approaches for the direct α-hydroxylation of branched ketones.

Nitrosobenzene has been used as an oxidant in organocatalytic aminoxylations of aldehydes and ketones.[5] In fact, in the presence of a Brønsted acid, a second equivalent of nitrosobenzene can additionally act as a reductant, giving direct access to the desired hydroxy carbonyl compounds via a tandem aminoxylation/N–O bond-cleavage process with azoxybenzene as the side product.[6]

Given the dearth of direct α-hydroxylation methods and based on our current interest in α-functionalizations of branched ketones via Brønsted acid catalyzed enolizations (enol catalysis),[7] we pursued a complementary method for the direct α-hydroxylation of branched ketones using nitrosobenzene. This reaction presents several challenges, i.e., i) controlling the regioselectivity of the enolization, as well as the ii) chemoselectivity (enol addition to O vs. N of nitrosobenzene) and finally, iii) successfully completing the tandem sequence.

We began our investigations using 2-phenylcyclohexanone (1a) as the model substrate (Table [1], for more details, see the Supporting Information). Optimization of the reaction conditions showed that an overstoichiometric amount of a strong acid is necessary for the reaction to proceed, with 3 equiv of trichloroacetic acid (TCA) giving the best result (Table [1], entry 4, 60% yield). Interestingly, weaker acids, e.g. acetic acid, did not show any reactivity (Table [1], entry 1). While the yield remained the same, higher amounts of TCA required additional purification steps to remove the excess of acid (Table [1], entry 7). Since clean reaction profiles were observed, we suspect the moderate yields to result from the formation of an uncharacterized polymer in the course of the reaction.

Table 1 Optimization of Reaction Conditions^a

Entry	Acid	equiv	Yield (%)b
1	AcOH	3	0
2	ClCH2CO2H	3	traces
3	Cl2CH2CO2H	3	28
4	Cl3CCO2H	3	(60)
5	F3CCO2H	3	(37)
6	Cl3CCO2H	1	27
7	Cl3CCO2H	5	(60)

^a Reaction conditions: 1a (0.25 mmol, 1.0 equiv), acid, nitrosobenzene (0.63 mmol, 2.5 equiv) in dry PhMe (2.5 mL).

^b Determined by ¹H NMR spectroscopy using Ph₃CH as internal standard. Isolated yield in parentheses.

With the optimized conditions in hand, we turned our attention towards the scope of this transformation. Various α-aryl cyclohexanones reacted readily under the reaction conditions giving the desired products in moderate to good yields (Scheme [2, 2a–q]). Interestingly, no significant electronic effect was observed (2f, 56% yield vs. 2g, 54% yield). To our delight, challenging ortho-substituted α-aryl cyclohexanones (2b and 2p), a cycloheptanone (2r) and 2-alkyl cyclohexanones (2u–w) could be transformed to their corresponding 2-hydroxy derivatives in similar yields. Furthermore, 2-methyl-indanone and 2-methyl-tetralone gave the desired products with similarly good results (2s, 64% and 2t, 61%). However, when cyclopentanones or acyclic ketones were used as substrates, no desired products were obtained. Finally, the robustness of the method was demonstrated by scale-up experiments of the model substrate. Gratifyingly, 2a was obtained at a maximum tested scale of 10 mmol without deterioration of yield.

Scheme 2 Scope of the α-hydroxylation of 2-substituted cyclic ketones, indanone and tetralone. If not otherwise indicated the reactions were performed using 0.25 mmol of 2. ^a Performed using 10 mmol of 2a.

To demonstrate the utility of our developed method, product 2a was derivatized to a variety of synthetically useful functionalities (Scheme [3]). Namely, amino alcohol 3 was obtained via reductive amination. Reduction of ketone 2a using K-Selectride^® gave diol 4 in excellent yield and dia­stereoselectivity. Notably, using NaBH₄ as the reductant ­resulted in similar yields, however, a dr of only 4:1 of the resulting diol was observed. Treatment of product 2a with methyl magnesium chloride resulted in the formation of diol 5 as a single diastereomer. Elimination under acidic conditions gave enone 6 in 54% yield, in addition to 16% of the corresponding regioisomeric enone (see the Supporting Information for details). Finally, treatment with the Bestmann ylide[8] afforded lactone 7, providing an efficient ­access to dihydroactinidiolide-type structures.[9]

Scheme 3 Chemical derivatization of obtained products. i) MeNH₂, Ti(OiPr)₄, PhMe, reflux, 24 h then NaBH₄, MeOH, 0 °C, 1 h. ii) K-Selectride^®, THF, –78 °C to 0 °C, 2 h then NaOH, H₂O₂, r.t., overnight. iii) MeMgCl, THF, –78 °C to r.t., overnight, the product was obtained as a mixture with unreacted starting material (¹H NMR ratio: 5.6:1). iv) pTsOH, PhMe, reflux, overnight. v) Ph₃PCCO, PhMe, reflux, 3 d.

In summary, we have developed a simple and practical Brønsted acid mediated direct hydroxylation of branched ketones using nitrosobenzene as the oxygen source.[10] The scope includes various 2-aryl and 2-alkyl cyclohexanones, which were converted into the corresponding products in moderate to good yields. The method is complementary to published systems, easy to execute, and scalable and therefore might find application in chemical synthesis.

• References and Notes

• 1a Edwards MG. Kenworthy MN. Kitson RR. A. Scott MS. Taylor RJ. K. Angew. Chem. Int. Ed. 2008; 47: 1935
• 1b Palomo C. Oiarbide M. Garcia JM. Chem. Soc. Rev. 2012; 41: 4150
• 1c Taj RA. Green JR. J. Org. Chem. 2010; 75: 8258
• 2 Smith AM. R. Hii KK. Chem. Rev. 2011; 111: 1637

For commonly applied methods, see:
• 3a Davis FA. Chen BC. Chem. Rev. 1992; 92: 919
• 3b Rubottom GM. Vazquez MA. Pelegrina DR. Tetrahedron Lett. 1974; 15: 4319

For selected publications regarding the direct α-hydroxylation of α-branched ketones, see:
• 4a Schulz M. Kluge R. Sivilai L. Kamm B. Tetrahedron 1990; 46: 2371
• 4b Ishikawa T. Hino K. Yoneda T. Murota M. Yamaguchi K. Watanabe T. J. Org. Chem. 1999; 64: 5691
• 4c Chuang GJ. Wang W. Lee E. Ritter T. J. Am. Chem. Soc. 2011; 133: 1760
• 4d Liang Y.-F. Jiao N. Angew. Chem. Int. Ed. 2014; 53: 548
• 4e Liang Y.-F. Wu K. Song S. Li X. Huang X. Jiao N. Org. Lett. 2015; 17: 876
• 4f Chen T. Peng R. Hu W. Zhang F.-M. Org. Biomol. Chem. 2016; 14: 9859
• 4g Tsang AS. K. Kapat A. Schoenebeck F. J. Am. Chem. Soc. 2016; 138: 518
• 4h Sim S.-BD. Wang M. Zhao Y. ACS Catal. 2015; 5: 3609

For selected reviews on organocatalytic aminoxylations, see:
• 5a Merino P. Tejero T. Delso I. Matute R. Synthesis 2016; 48: 653
• 5b Vilaivan T. Bhanthumnavin W. Molecules 2010; 15: 917
• 5c Janey JM. Angew. Chem. Int. Ed. 2005; 44: 4292
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• 6b Lu M. Zhu D. Lu Y. Zeng X. Tan B. Xu Z. Zhong G. J. Am. Chem. Soc. 2009; 131: 4562

For publications regarding enol catalysis by our group, see:
• 7a Felker I. Pupo G. Kraft P. List B. Angew. Chem. Int. Ed. 2015; 54: 1960
• 7b Shevchenko GA. Pupo G. List B. Synlett 2015; 26: 1413
• 7c Pupo G. Properzi R. List B. Angew. Chem. Int. Ed. 2016; 55: 6099
• 7d Shevchenko GA. Oppelaar B. List B. Angew. Chem. Int Ed. 2018; 57: 10756

For independent contributions from other groups, see:
• 7e Pousse G. Le Cavalier F. Humphreys L. Rouden J. Blanchet J. Org. Lett. 2010; 12: 3582
• 7f Burns AR. Madec AG. E. Low DW. Roy ID. Lam HW. Chem. Sci. 2015; 6: 3550
• 7g Yang X. Toste FD. J. Am. Chem. Soc. 2015; 137: 3205
• 7h Yang X. Toste FD. Chem. Sci. 2016; 7: 2653
• 7i Spanka M. Schneider C. Org. Lett. 2018; 20: 4769

For an account on heterodimeric activation in organocatalysis, see:
• 7j Monaco MR. Pupo G. List B. Synlett 2016; 27: 1027
• 8 Bestmann HJ. Angew. Chem., Int. Ed. Engl. 1977; 16: 349
• 9a Rocca JR. Tumlinson JH. Glancey BM. Lofgren CS. Tetrahedron Lett. 1983; 24: 1889
• 9b Rubottom GM. Juve HD. J. Org. Chem. 1983; 48: 422
• 9c Yao S. Johannsen M. Hazell RG. Jørgensen KA. J. Org. Chem. 1998; 63: 118
• 9d Eidman KF. MacDougall BS. J. Org. Chem. 2006; 71: 9513
• 10 Exemplary Procedure In a GC vial 2-phenylcyclohexanone (1a, 43.6 mg, 0.25 mmol, 1.0 equiv) was dissolved in a solution of trichloroacetic acid (0.75 mmol, 3.0 equiv) in dry PhMe (2.5 mL) and nitrosobenzene (0.625 mmol, 2.5 equiv) was added. The vial was closed with a screw cap, and the resulting mixture was stirred at r.t. for 16 h. The crude reaction mixture was directly purified by flash column chromatography (SiO₂, hexanes/EtOAc = 100:0 then 10:1) to give 2-hydroxy-2-phenylcyclohexan-1-one (2a) as an orange oil (28.7 mg, 60%). ¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.27 (m, 2 H), 7.35–7.29 (m, 3 H), 5.04 (s_br, 1 H), 3.06–2.99 (m, 1 H), 2.59–2.51 (m, 1 H), 2.48–2.39 (m, 1 H), 2.11–2.02 (m, 1 H), 1.91–1.83 (m, 2 H), 1.82–1.68 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 212.9, 139.8, 129.3, 128.6, 126.5, 80.3, 39.0, 38.9, 28.5, 23.2. HRMS (ESI+): m/z calcd for C₁₂H₁₄O₂Na [M + Na]⁺: 213.0886; found: 213.0885.