Aminium Cation-Radical Catalysed Selective Hydration of (E)-Aryl Enynes

Abstract

The hydration of carbon-carbon triple bonds is an important and atom economic synthetic transformation. Herein, we report a mild and selective method for the catalytic Markovnikov hydration of (E)-aryl enynes to the corresponding enones, mediated through the bench-stable aminium salt, tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA). The chemoselective and diastereoselective method proceeds under neutral metal-free conditions, delivering excellent product yields from terminal and internal alkyne units. The synthesis of biologically important (E)-3-styrylisocoumarins, including a formal synthesis of the natural product achlisocoumarin III, demonstrates the utility of this novel transformation.

Alkyne hydration¹ is an important, atom economical² reaction with enormous significance in organic synthesis. First reported over 150 years ago, classical hydration reactions require strong protic acids such as H₂SO₄ to overcome the activation barriers of the otherwise exergonic process.³

Mechanistically, the hydration of a terminal alkyne follows either a Markovnikov addition pathway to give the ketone or the anti-Markovnikov route to an aldehyde; non-symmetrical internal alkynes, on the other hand, can lead to mixtures of both possible ketone regioisomers (Fig. 1). The discovery by Kucherov in 1881⁴ of the rate acceleration of alkyne hydration by mercury(II) salts had a significant impact in synthetic¹ and industrial applications.⁵ However, the use of toxic mercury salts is undesirable, particularly for large-scale applications, and several environmentally friendlier protocols have emerged.^{1, 6–16}

Fig. 1.

A) Classical Brønsted acid and Kucherov-type alkyne hydration protocols; B) This work: TBPA aminium cation-radical mediated hydration of (E)-aryl enynes.

Herein, we report a mild, atom economical, and metal-free protocol for the hydration of aryl enynes using aminium ion catalysis. The (E)-enyne selective method delivers the Markovnikov hydration products with (E)-configuration in excellent yield.

The selective hydration of enynes to enones presents a significant challenge due to competing alkene hydration potential.¹⁵ The few examples that have been reported require either strong Brønsted acids^15a or mercury(II) salt catalysts.¹⁷ During our work on single-electron transfer reactions,¹⁸ we made an observation that led us to envisage a new approach for enyne hydration mediated through a cation-radical initiated pathway. In the presence of the aminium cation-radical salt tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA; Ledwith-Weitz salt),¹⁹ (E)-1-(but-1-en-3-yn-1-yl)-4-methoxybenzene (1) underwent hydration to the aryl enone 2 in trace quantities (Table 1). The following optimised protocol was subsequently developed: [0.1 eq. of TBPA, stirring for 2 h at40 °C in reagent grade acetone that had been purged with nitrogen gas] that increased the overall yield of the enone 2 to 74% (Table 1, entry 5). A trace quantity of product 3, thought to arise through an aldol condensation process between 2 and acetone was also observed. Interestingly, when high purity acetone²⁰ was used as the solvent, the yield of 2 was significantly reduced (28%). However, the addition of 1.0 equivalent of water to the high purity acetone resulted in 78% yield of the product (cf. 74% yield using reagent grade “wet” acetone). Gradually increasing the water content up to 5.0 equivalents led to a steady reduction in the yield (7%) (See SI, T1), which is likely due to the degradation of the catalyst through reaction with water, resulting in the neutral tris(4-bromophenyl)amine.^21,22 Introducing oxygen to the solvent also resulted in lower product yields, and we find it necessary to purge the solvent mixture with nitrogen gas before introducing the TBPA. When the enyne 1 was taken into high purity acetone followed by the addition of 1.0 eq. of H₂¹⁸O and TBPA catalyst, the ¹⁸O labelled hydration product was detected by electrospray ionization (ESI) mass spectrometry, suggesting water is the source of the incorporated oxygen (See SI).

Table 1.

Optimisation of aminium cation radical-mediated enyne hydration.^a

Entry	Solvent	W (mol%)	Temperature (T)/°C	Time (X)/h	Yield (%) of 2	Yield (%) of 3
1	CH2Cl2	10	0	1	Trace	0
2	CH2Cl2	10	40	1	Trace	0
3	THF	10	40	2	0	0
4	MeCN	10	40	2	14	0
5	Acetone	10	40	2	74	Trace

^[a]The reactions were performed on a 0.20 mmol scale; isolated yields.

The method performs well with both terminal and internal (E)-aryl enynes and is tolerant of several functional groups, including Cl (4l), I (4m), OAc (4n), OTs (4o); each giving consistently high yields of the aryl enone products (5l-5o) (Scheme 1A). The specificity for enynes over alkynes is particularly noteworthy — in the case of 4c, the propynyloxy group was unaffected by the hydration conditions, giving the enone product 5c in 78% yield. The TBPA mediated reaction of the enynol substrates 4p and 4q resulted in the 2,2-dimethyltetrahydrofuran-3-yl products 5p (43%) and 5q (29%), respectively. The tetrahydrofuran ring structure of 5q was corroborated through single-crystal X-ray crystallography of the 4-nitrobenzoate derivative 5r (Scheme 1B). Both 5p and 5q presumably incorporate acetone through an aldol-typeprocess, followed by intramolecular cyclisation. Interestingly, when the (Z)-enynes 4s and 4t were exposed to the optimised reaction conditions, no hydration products were detected, suggesting a high level of selectivity (Scheme 1C).

Scheme 1.

Substrate scope for the aminium cation radical-mediated hydration protocol. [a] The reactions were performed on a 0.20 mmol scale; isolated yields. [b] Reaction performed at 50 °C. [c] Reaction proceeded for 3 h. [d] Reaction performed on 0.40 mmol scale. [e] Reaction performed on 0.29 mmol scale. [f] Reaction performed on 0.41 mmol scale. [g] Reaction performed on 0.34 mmol scale. [h] Reaction performed at 45 °C. [i] Reaction performed on 0.94 mmol scale. [j] No product observed. Compound 5r was synthesised from 5q in two steps; i: TBAF (1.0 M in THF) (1.4 eq.), THF, r.t., 5 min, 94%, ii: 4-nitrobenzoyl chloride (1.00 eq.), Et₃N (2.05 eq.), CH₂Cl₂, 0 °C - r.t., 0.5 h, 70% (See SI for experimental procedures)

Mechanistically, TBPA mediated reactions are considered to follow: i) a cation-radical mediated pathway,²³ and/or ii) a classic Brønsted acid directed process.²⁴ To investigate, we performed the TBPA mediated hydration of enyne 1 in the presence of 2,6-di-tert-butyl-4-methylpyridine (20 mol%) according to Gassman’s test.^23c,24 The outcome remained unchanged — the hydration product was obtained in a comparable 68% yield — suggesting that Brønsted acid catalysis was unlikely.

While details of the reaction mechanism are yet to be fully elucidated, we tentatively propose the catalytic cycle illustrated in Scheme 2 to rationalise the selective hydration of (E)-aryl enynes and the formation of related products. Initiation of the cation-radical mediated process is presumed to proceed by oxidation of the (E)-enyne 4 by TBPA to give the cation-radical [SbCl₆]^- intermediate 6. Nucleophilic attack by water on intermediate 6 gives the cation-radical enol intermediate 7, that upon tautomerisation delivers the ketone intermediate 8. Reduction of 8 through single-electron transfer from the triarylamine (or an equivalent species) yields the (E)-aryl enone 5 along with regeneration of TBPA.^23,25 Alternatively, and consistent with the work of Mares and co-workers,²⁶ it is feasible that the cation-radical intermediates 7 and/or 8 (or related, e.g., 6) could be chain propagating species with TBPA functioning as the initiator.

Scheme 2.

A plausible working mechanism for the TBPA catalysed hydration of the (E)-aryl enynes.

The formation of the 2,2-dimethyltetrahydrofuran-3-yl products (e.g., 5p, where R = -CH₂CH₂OH) can be rationalised by the reversible aldol-type condensation of 7 with acetone to give intermediate 9, followed by dehydrative cyclisation. When R = H, aldol condensation of 7 with acetone explains the origin of the side product 10. The observed (E)-selectivity of the reaction can be rationalised by considering the relative oxidation potential of the conjugated (E/Z)-aryl enynes and stability of the resulting cation-radical intermediate species.²⁷

The SbCl₆^- counterion was found to be important for the hydration reaction; when replaced with tris(4-bromophenyl) aminium hexafluorophosphate, no reaction was observed. This is consistent with the report of Ledwith and co-workers¹⁹ on the stabilising influence of the hexachloroantimonate anion due to reoxidation of the neutral amine.

To showcase the potential utility of the new methodology, we selected the important 3-styryliscoumarin core, which is a prevalent motif in several natural products.^28–31 We envisaged a pathway where enyne hydration of 11 is followed by cyclisation of the enol tautomer 12 to deliver the 3-styryliscoumarin core 13 (Scheme 3). Using methyl (E)-2-(4-(2,4-dimethoxyphenyl)but-3-en-1-yn-1-yl)benzoate (11a) as a model substrate with 10 mol% TBPA at 50 °C for 1 h, the styrylisocoumarin (13a) was isolated in 82% yield. A selection of methyl (E)-2-(4-phenylbut-3-en-1-yn-1-yl) benzoate derivatives (12) were subsequently converted to the corresponding (E)-3-styrylisocoumarins (13) in good yield (30–82%) under the mild reaction conditions. Notably, the synthesis of (E)-3-styrylisocoumarin 13j constitutes a formal synthesis of the natural product, achlisocoumarin III (13k).^29b

Scheme 3.

Investigation into substrate scope of 1,4-diarylenynes (12). [a] The reactions were performed on a 0.20 mmol scale; isolated yields. [b] Reaction performed for 7 h.

In summary, we have developed a novel and selective method for the hydration of conjugated (E)-aryl enynes catalysed by the cation-radical salt TBPA. The new protocol abets the hydration of both terminal and internal conjugated enynes in good to excellent yield. The aryl enone hydration products are prized synthetic intermediates with the ability to undergo a range of valuable chemistries including intramolecular cyclisation to yield isocoumarin-type cores. The application of the methodology was showcased in the formal synthesis of the 3-styrylisocoumarin natural product, achlisocoumarin III. We believe the novel aminium radical mediated hydration method is a valuable addition to the toolbox of alkyne reactivity, offering a new mild and selective pathway to useful synthetic intermediates.