Pd-Catalyzed Acyl C–O Bond Activation for Selective Ring-opening of α-Methylene-β-lactones with Amines

Abstract

A Pd-catalyzed ring-opening of β-lactones with various types of amines (primary, secondary and aryl) to provide β-hydroxy amides with excellent selectivity towards acyl C–O bond cleavage is reported. The utility of this protocol is demonstrated in an asymmetric kinetic resolution providing enantioenriched α-Methylene-β-lactones

Graphical abstract

β-lactones are important intermediates in organic synthesis.¹ They can be readily accessed in high enantiomeric purity, and they undergo a broad range of transformations, providing highly functionalized products. As part of our interest in the utility of β-lactones or β-lactone-derived strained heterocycles in organic synthesis, we have reported several of their reactions in the presence of transition metal (TM) catalysts.² In particular, we reported that α-Methylene-β-lactones 1 readily undergo cross-metathesis reactions^2e and recently used this to access a focused library of 3,4-disubstituted β-lactones for proteomic profiling.^2c,d A current interest is to develop further useful methods employing 1, especially applications involving ring-opening reactions.

The ring-opening of β-lactones with different nucleophiles has been utilized in the synthesis of biologically important synthetic and natural products. Nevertheless, a major problem in opening β-lactones can be the formation of two isomeric products due to competing alkyl C–O and acyl C–O bond cleavages (Figure 1A).^1a In particular, the selective opening of β-lactones with amines has proven to be challenging.³ We hypothesized that α-Methylene-β-lactones 1 could undergo selective ring opening with amine nucleophiles under Pd catalysis (Figure 1B). These unsaturated β-lactones could be expected to undergo allyl C–O bond activation with Pd to provide palladacycle A⁴ (Figure 1B, path a). Alternatively, the olefin could act as a directing group⁵ to facilitate the oxidative addition of Pd into the acyl C–O bond to form palladacycle B (Figure 1B, path b). Herein the development of a Pd-catalyzed activation of α-Methylene-β-lactones to provide solely β-hydroxy-α-Methyleneamides in good to excellent yields is reported. The broad scope of the transformation using various β-lactones and amines is described.

Figure 1.

Alkyl vs acyl C–O bond cleavage in β-lactones.

As mentioned above, we postulated that selective opening of α-Methylene-β-lactones might be promoted by oxidative addition of a TM into either the alkyl or acyl C–O bond. There is direct precedent for alkyl C–O bond activation of β-lactones. Puddephatt reported the oxidative addition of oxetan-2-one with a stoichiometric amount of a Pt complex via alkyl C–O cleavage (Figure 2).⁶ Noels described a Pd-catalyzed opening of vinyl-substituted β-lactones to form butadiene acids.⁷ This transformation was proposed to involve allyl C–O bond activation to form a palladalactone which then undergoes β-hydride elimination. This mode of activation was utilized by Hattori with vinyl β-lactones generated in situ from the reaction of ketene with α,β-unsaturated aldehydes.⁸ These allylic systems would appear to be especially relevant to an expectation that Pd-catalysis might be used for alkyl C–O bond cleavage in α-Methylene-β-lactones.

Figure 2.

Transition metal activation of alkyl C–O bonds in β-lactones.

There are, to our knowledge, no reports of TM-catalyzed ring opening of β-lactones at the acyl C–O bond. Consequently we looked into TM-catalyzed coupling of esters with amines. Certain types of esters, activated with α-aromatic/heteroaromatic or CF₃ substituents or certain alkoxy moieties, have been shown to undergo TM-catalyzed acyl C–O bond activation. The intermediates can be cross-coupled to form ketones⁹ or undergo decarbonylation¹⁰ before reductive coupling. Of potential direct relevance, Bao and coworkers recently developed a Pd-catalyzed amidation of activated esters that was believed to involve an acyl C–O insertion with a Pd catalyst.¹¹ Also, the Garg group utilized a nickel catalyst for the activation of aromatic methyl esters for amide formation.¹² We surmised that the α-Methylene could play the role of an activating group for C–O insertion.

We initially probed the ring-opening of α-Methylene-β-lactone 1a with benzylamine in the presence of a catalytic amount of Pd(OAc)₂ and PPh₃ in DCM at rt (Table 1). The use of 2 equivalents of benzylamine provided a 4:1 mixture of β-hydroxy amides 3a and 4 (entry 1). The latter was believed to arise from aza-Michael addition of the excess amine to product 3a. After optimization of the concentration and of the molar ratio of benzylamine, 3a was isolated in 92% yield (entry 2). At 45 °C, complete conversion was achieved after 12 h, providing 3a in nearly quantitative yield. Other solvents, such as THF and CHCl₃, as well as biphosphine ligands (BINAP and SEGPHOS), gave outcomes similar to entry 2. Other Pd sources (entries 4 to 6) also promoted the transformation. Notably, the use of catalytic Pd(PPh₃)₄ without exogenous phosphine ligand provided an efficient conversion, but 3a and 4 were formed in a 10:1 ratio. When the reaction was carried out in the absence of Pd catalyst or phosphine ligand (entries 7–9), no significant conversion was observed. It is also worth noting that the other possible product, β-amino acid 2 (Figure 1B, path a) was never observed. Consistent with our alternate hypothesis (Figure 1B, path b), these results indicate that the reaction is promoted by initial oxidative addition of Pd(0) to the acyl C–O bond of β-lactone 1.

Table 1. Initial Studies on the Pd-Catalyzed Amidation of β-Lactone 1a with Benzyl Amine^a.

entry	variation from general conditions	ratio 3a:4b	yield 3ac
1	2 equiv of BnNH2, 0.5 M	4:1	80%
2	none	>20:1	92%
3	45 °C, 12 h	>20:1	98%
4	2 mol % [Pd(allyl)Cl]2; 12 mol % PPh3	>20:1	90%d
5	2 mol % Pd2(dba)3; 12 mol % PPh3	>20:1	95%d
6	5 mol % Pd(PPh3)4; no PPh3	10:1	85%d
7	5 mol % Pd2(dba)3; no PPh3	-	n. r.e
8	no Pd(OAc)2	-	<5% convb
9	no PPh3	-	∼10% convb

^aGeneral conditions: 0.1 mmol 1a, benzylamine (1.1 equiv), Pd catalyst (5 mol % Pd(OAc)₂), 15 mol % PPh₃ in DCM (0.2 M) atrt for 24 h.

^bRatios and conversions were estimated by ¹H NMR analysis of the crude reaction mixture.

^cIsolated yields except where noted.

^d1H NMR yields using 1,3,5-trimethoxybenzene as internal standard.

^eThe starting material was recovered; Pd black was observed on the wall of the reaction tube.

The optimized conditions shown in the reaction scheme in Table 1 were utilized for the ring-opening of several α-Methylene-β-lactones with various types of amines. As highlighted in Scheme 1, primary, secondary and allyl amines provided β-hydroxy amides 3a-f in good to excellent yields. The outcome observed with morpholine (3e) is noteworthy. Adam and coworkers found that cyclic, secondary amines (such piperidine and pyrrolidine) reacted with α-Methylene-β-lactones in the absence of a Pd catalyst to give conjugate addition products.¹³

Scheme 1. Scope of Pd-Catalyzed Amidation of α-Methylene-β-lactones^a with Various Amines^b.

^aFor the syntheses of the α-Methylene-β-lactones see the Supporting Information. ^bGeneral conditions: 0.1 to 0.2 mmol 1 (1 equiv), amine (1.1 equiv), Pd(OAc)₂ (5 mol %), PPh₃ (15 mol%) in DCM (0.2 M) at rt or 45 °C for 24 h. For aryl amines: 2-4 equiv of aryl amine was used in DCM (0.5 M) at 45 °C. ^c1.0 mmol scale.

Aryl amines were also successfully coupled to give exclusively the corresponding amides. When these amines were used in excess (2-4 equivalents), and the reaction was conducted at 45 °C β-hydroxy-α-Methylene arylamides 3g-j were obtained in high yields.

To extend the generality of this method, we next explored whether the Pd-catalyzed ring-opening can be used for simple β-lactones. As shown in Scheme 2, α-phenyl-β-lactone 4 underwent facile ring-opening with benzylamine, providing the ring-opened product in excellent yield at rt. Racemic trans-disubstituted β-lactone 5 also gave the desired product with complete selectivity, albeit in slightly lower yield. Notably, when β-lactone 4 or 5 was reacted with benzylamine in the absence of a Pd catalyst, the reaction was messier (based on ¹H NMRs of crude reaction mixtures), and the isolated yield for 3k (65%) or 3l (52%) was lower. Homochiral β-lactone (R)-1a (99% ee) also underwent ring opening to yield β-hydroxy amide (R)-3a (99% ee) without erosion of stereochemical integrity. Likewise, α-alkylidene-β-lactone 6, prepared by the Ru-catalyzed cross-metathesis of its corresponding α-Methylene-β-lactone,^2e provided α-alkylidene-β-hydroxy amide with complete retention of olefin geometry.

Scheme 2. Scope of Pd-Catalyzed Amidation of Various Types of β-lactones^a.

^aFor the syntheses of the β-lactones see the Supporting Information. General conditions: 0.2 mmol 1 (1 equiv), amine (1.1 equiv), Pd(OAc)₂ (5 mol %), PPh₃ (15 mol %) in DCM (0.2 M) at rt or 45 °C for 24 h.

To date, enantioenriched α-Methylene-β-lactones 1 have only been accessed via enzymatic kinetic resolution.¹⁴ Our interest in α-Methylene-β-lactones 1 as privileged intermediates in organic synthesis led us to explore the Pd-catalyzed amidation for potential resolution of racemic β-lactones. Several chiral phosphine ligands typically used in asymmetric Pd-catalyzed C–N bond coupling reactions were evaluated (Scheme 3). Racemic β-lactone 1a underwent efficient amidation. Reactions were monitored by ¹H NMR analysis and were quenched after obtaining ∼50-55% conversions, typically after 16 to 20 h. (R)-BINAP and (R)-SEGPhos (not shown) did not provide any selectivity. When chiral Trost ligands ¹⁵ L2 and L3 were utilized, 5–38% ee's were obtained. The use of chiral spiroketal phosphine (SKP) ligands, recently developed by Ding and co-workers,¹⁶ provided improved resolution, up to 68% ee (using SKP-L4). Further optimization (such as the use of various Pd sources, solvents, type and amounts of amine, reaction concentration, and temperature) did not improve the enantioselectivities. The conditions developed above for Pd-catalyzed asymmetric kinetic resolution were utilized for other β-lactones. With the exception of α-phenyl-β-lactone 4, good yields and moderate enantioselectivities were obtained.

Scheme 3. Pd-Catalyzed Asymmetric Kinetic Resolution of β-lactones^a.

^aGeneral conditions: 0.1 to 0.2 mmol 1 (1 equiv), amine (1 equiv), Pd(OAc)₂ (2 mol %), chiral ligand (5 mol %) in CDCl₃ (0.2 M) at rt for 16 to 20 h.

In conclusion, we have developed a highly selective Pd-catalyzed ring opening of α-Methylene-β-lactones and β-lactones with various types of amines (primary, secondary, and aryl) to give amides via acyl C–O activation. The complete chemoselectivity and efficiency of the transformation are remarkable. Moreover, enantioenriched α-Methylene-β-lactones can be obtained through kinetic resolution by using chiral phosphine ligands. The kinetic resolution of α-Methylene-β-lactones has previously only been achieved by an enzymatic process.