A Regio- and Enantioselective CuH-Catalyzed Ketone Allylation with Terminal Allenes

Abstract

We report a method for the highly enantioselective CuH-catalyzed allylation of ketones that employs terminal allenes as allylmetal surrogates. Ketones and allenes bearing diverse and sensitive functional groups are efficiently coupled with high stereoselectivity and exclusive branched regioselectivity. In stoichiometric experiments, each elementary step of the proposed hydrocupration–addition–metathesis mechanism can be followed by NMR spectroscopy.

Graphical Abstract

Chiral alcohols and their derivatives are common and essential substructures in biologically active compounds. Thus, reactions that generate alcohols in a stereoselective manner represent fundamental transformations in organic synthesis. In particular, the nucleophilic addition of an allyl group to carbonyl compounds, producing synthetically versatile homoallylic alcohols, has been a subject of extensive investigation.¹ Despite the invention of several successful implementations, such approaches usually require the prior preparation of superstoichiometric quantities of an allylmetal reagent in a separate operation.^2–12 Often, this process is itself required to be highly stereoselective in order for the subsequent allylation step to be effective.

Although general solutions exist for simple nucleophiles, such as allyl-, crotyl-, or cinnamyl metal complexes, ¹³ practical reagents for installation of complex allyl fragments are rare, and their synthesis typically requires the use of strong bases, restricting compatibility with acidic or polar functional groups.⁵ As an alternative, we considered a process in which a chiral organometallic reagent assembles catalytically from an olefin and subsequently engages a ketone stereoselectively within a single mechanistic cycle.

Recently, our laboratory has reported several methods involving in situ generation of organocopper nucleophiles via the hydrocupration of unsaturated substrates.^14,15 Originally developed in the context of hydroamination reactions, ^15l,m this hydrometalation–functionalization strategy has also found success in reductive coupling with carbon-centered electrophiles, most notably imines^15e,f and ketones. ^15g In the context of allylation specifically, we were inspired by pioneering work by Krische and others using aldehydes and activated ketones.^16–24 In general, however, typical ketones are challenging electrophilic partners for stereoselective coupling relative to aldehydes, due to their attenuated reactivity and minimal steric differentiation between the carbonyl substituents.

Our proposal, described in Figure 1B, takes advantage of the ability of phosphine ligated copper hydride complexes to catalytically generate a mixture of allylcopper species when exposed to terminal allenes.^{11a,11c,11f,15e} Notably, the rate of this process needed to surpass the rate of direct ketone reduction, which has been shown to be a fast process. ^24–26 Based on theoretical studies on the addition of these nucleophiles to imines,^15e we anticipated allyl addition to ketones would take place with exclusive branched regioselectivity.^15e To complete the catalytic cycle, the initial hydride complex would be regenerated either by direct metathesis with a hydrosilane, or via intermediate ligand exchange with an auxiliary alcohol.

Figure 1.

Overview of metal-catalyzed reductive allylation reaction of ketones using terminal allenes.

Initial investigations of this transformation were focused on reacting acetophenone (1a) with cyclohexyl-allene (1b) under previously described reaction conditions for imine allylation (Table 1, entry 1). With a simple achiral supporting ligand, the desired product 1 was obtained in high yield, with exclusive branched-selectivity, and with moderate preference for the indicated diastereomer (5:1 dr). When the ligand was exchanged for chiral phosphine (S,S)-Ph-BPE B, high enantioselectivity was also obtained (Table 1, entry 2). Lowering the reaction temperature slightly and switching the solvent to toluene proved to be beneficial (Table 1, entries 3 and 4). Further evaluation of common chiral ligands revealed JOSIPHOS-type phosphine D²⁷ to be optimal (Table 1, entry 7). The effect of tert-butanol on the observed diastereo- and enantioselectivity is notable, although its role remains unclear (Table 1, entry 8).

Table 1.

Evaluation of Reaction Conditions for the CuH-Catalyzed Allylation of Acetophenone.^a

Entry	Ligand	Solvent	Temp (°C)	Yieldb 1 (%)	eec (%)
1	A	THF	25	95 (5:1 dr)	-
2	B	THF	25	90 (7:1 dr)	87
3	B	THF	0	91 (8:1 dr)	89
4	B	CyH	0	50 (5:1 dr)	89
5	B	PhMe	0	95 (8:1 dr)	90
6	C	PhMe	0	76 (10:1 dr)	91
7	D	PhMe	0	97 (14:1 dr)	96
8d	D	PhMe	0	90 (9:1 dr)	92
9	E	PhMe	0	50 (2:1 dr)	15

^aConditions: 0.1 mmol ketone (1 equiv), allene (2 equiv), copper(II) acetate (0.05 equiv), ligand (0.06 equiv), dimethoxy( methyl)silane (5 equiv), tert-butanol (2 equiv) in solvent (0.2 mL); see the Supporting Information for details.

^bYield and diastereomeric ratio was determined by ¹H NMR spectroscopy of the crude mixture, using 1,1,2,2-tetrachloroethane as internal standard.

^cEnantiomeric excess was determined by HPLC or SFC analysis on commercial chiral columns.

^dReaction conducted without tert-butanol.

Upon scaling up the optimal conditions to preparative quantities of material, we found that only a small excess of allene (1.2 equiv) and DMMS (2 equiv)²⁸ were necessary to obtain high yields and selectivity, for instance in the case of model compound 1 (Table 2). The reaction proceeded efficiently with substrates bearing electron-donating (3, 4) or electron-withdrawing (6) substituents, although 5 was only obtained in moderate yield. Acetophenones bearing ortho-substituents were converted successfully, as well as symmetrical (9) or cyclic (10) ketones. Furthermore, substrates containing heterocycles (11–14) and those with functional groups such as a free hydroxyl group (4), a secondary amine (3), aryl halides (6, 12), a sulfonyl protecting group (14), and tert-butyl ester (5) were all tolerated under the reaction conditions, providing opportunities for further elaboration. Finally, dialkyl ketone 15 was converted, notably with high diastereoselectivity considering the steric similarity of the methyl and methylene substituents on the ketone. In all cases, the reaction proceeded with useful to good enantioselectivity. A crystal structure of 14 showed the absolute configuration of the major enantiomer to be (S) at the tetrasubstituted stereocenter and (R) at the adjacent methane. We note that the relative configuration of these stereocenters is consistent with addition through a chair-like 6-membered transition state.

Table 2.

Evaluation of Ketone Scope.

^aYields indicate isolated yield of product as a mixture of two diastereomers on a 0.5 mmol scale. 1.2 equiv of allene was used, see Supporting Information for further details. Diastereomeric ratios were determined by ¹H NMR spectroscopy for both the crude and purified products using 1,1,2,2-tetrachloroethane as internal standard;. Enantiomeric excesses determined by HPLC or SFC analysis on commercial chiral columns; enantiomeric ratios of minor diastereomers indicated in parentheses. Yields, diastereomeric ratios, and enantiomeric excesses are the averages for two identical runs.

^bThe reaction was conducted without tert-butanol;

^cThe diastereomeric ratio was determined using both GC and chiral SFC analysis.

We next assessed the scope of compatible allenes under these conditions. Unbranched (16) and 1,1-disubstituted (17) allenes are both coupled with high enantioselectivity. A commercial ether, methoxyallene, was employed effectively as a precursor for an (alkoxy)allylmetal nucleophile (18), which is rarely utilized in ketone additions even when prepared stoichiometrically. Various polar functional groups are tolerated well on the allene component, including an alcohol (19), an ester (20), and a secondary amide (21). An allene bearing a nitrogen heterocycle (22) reacted efficiently and with a high level of enantioselectivity. Under current conditions, however, addition of the parent allyl fragment derived from allene gas proceeds with only moderate selectivity (23).

We also carried out a number of experiments by NMR to corroborate the plausibility of our mechanistic proposal (Scheme 1). For the purpose of these studies, we chose the achiral, but kinetically competent ligand DCyPE (A) for these studies.

Scheme 1. Stoichiometric Observation of Relevant Reaction Intermediates by ³¹P NMR Spectroscopy.

Quantities shown in blue are chemical shifts of the phosphorus atoms in major species shown; see Supporting Information for details. (a) (MeO)₂MeSiH, benzene; (b) cyclohexylallene, benzene; (c) acetophenone, benzene; (d) (MeO)₂MeSiH.

The putative copper hydride complex was prepared stoichiometrically by addition of 1.0 equivalent of DMMS to phosphine ligated copper(I) acetate complex I. From here, addition of excess cyclohexylallene led to insertion, forming complex II with spectroscopic properties consistent with that of a linear allyl copper species (based on ¹H and ³¹P NMR spectroscopy, see Supporting Information). The observed linear allylcopper complex also has been previously predicted by DFT studies to be the lowest energy isomer.^15e As expected, addition of excess acetophenone resulted in insertion to form the copper-alkoxide complex III of the desired tertiary alcohol product. This complex can be reconverted into the initial hydride complex I directly upon addition of an excess of hydrosilane. Having observed each of the proposed intermediates by ³¹P NMR spectroscopy, we aimed to determine the resting state of the copper catalyst under the standard reaction conditions. Examination of the reaction mixture by ³¹P NMR spectroscopy during a catalytic reaction starting with DCyPE-ligated copper hydride complex I revealed a single resonance at 10.7 ppm matching the chemical shift of the copper allyl species II. Thus, we conclude that the catalyst is predominantly present in the allylcopper form under the typical reaction conditions. Therefore, since we propose that addition to the ketone is irreversible and stereoselectivity-determining, we suggest that this step is also turnover-limiting.

In summary, we have developed a mild, base-metal-catalyzed asymmetric allylation of ketones from terminal allenes. We anticipate that the chemoselective hydrocupration– 1,2-addition sequence demonstrated here will serve as a platform for the development of further synthetically useful transformations of unsaturated compounds.

Table 3.

Evaluation of Allene Scope.^a

^aYields indicate isolated yield of product as a mixture of two diastereomers on a 0.5 mmol scale, unless otherwise indicated. 1.2 equiv of allene was used, see Supporting Information for further details. Diastereomeric ratios determined by ¹H NMR spectroscopy of the crude mixture, using 1,1,2,2-tetrachloroethane as internal standard. Enantiomeric excesses determined by HPLC or SFC analysis on commercial chiral columns; enantiomeric ratios of minor diastereomers indicated in parentheses. Yields, diastereomeric ratios, and enantiomeric excesses are the averages for two identical runs.

^bThe reaction was conducted on a 0.1 mmol scale.