Main

Since the first report in 1964 (ref. 1), Fischer-carbene complexes (FCs) have evolved into powerful reagents for organic synthesis, encompassing cycloaddition, carbene transfer and addition reactions of electrophiles and nucleophiles2,3,4,5. Although transformations enabled by FCs are unique, their use in catalytic reactions lags far behind from those involving metal carbene species bearing an electron-withdrawing group6. This is primarily because common diazo compounds cannot be used as precursors due to their instability of the corresponding heteroatom-substituted derivatives7. Therefore, FCs are typically accessed by the addition of organolithium (RLi) to a metal–carbonyl complex (M–CO) and the subsequent capture with an alkyl halide (R′X) (Fig. 1a)2,4. A few catalytic reactions that involve FCs have been reported so far, including the addition of heteroatom nucleophiles to vinylidene complexes8,9,10,11,12, the substitution of Rh(II) carbenes bearing an iodonium leaving group by a tethered nucleophile13, and the trapping of photochemically generated siloxycarbenes from acylsilanes with a Cu(I) catalyst14,15. However, the scope of these catalytic protocols for FCs remains limited, and the vast majority of intriguing transformations mediated by FCs requires the use of stoichiometric amounts of metal reagents. Among such transformations that are awaiting a catalytic protocol is the chromium FC-mediated synthesis of β-lactam derivatives, which proceed via the photo-induced carbonylation of an alkoxycarbene ligand to form a ketene, followed by a [2 + 2] cycloaddition with imines (Fig. 1b)16,17,18,19,20.

Fig. 1: Background and the present study of FCs.
figure 1

a, Generation of FCs. b, Known stoichiometric reactions of FCs with imines. c, Palladium-catalysed carbonylative cycloaddition of acylsilanes with imines. d, Bioactive molecules containing α-hydroxy-β-lactams.

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We envisioned that this FC-mediated β-lactam synthesis might be conducted in a catalytic manner without photoirradiation based on a palladium/acylsilane reaction system (Fig. 1c). We previously reported on the palladium-catalysed siloxycyclopropanation of alkenes using acylsilanes, in which the oxidative addition of a C–Si bond triggers the in situ generation of a siloxycarbene–palladium intermediate21. If the thus generated siloxycarbene–palladium species would react with external CO to provide a ketene, this would lead to the formation of a β-lactam product without producing stoichiometric amounts of chromium waste or the need for photoirradiation22,23. The α-hydroxy-β-lactam skeleton24,25,26,27 that would be made accessible by this catalytic method represents a major motif that is found in a variety of bioactive substances (Fig. 1d)28. In this Article, we describe that a palladium-mediated protocol for the generation of a siloxycarbene–palladium intermediate from acylsilanes can be applied to the catalytic synthesis of β-lactams. An elusive siloxycarbene–palladium intermediate was isolated and characterized.

Results

Reaction development

Based on our previous studies on palladium-catalysed reactions of acylsilanes21,29,30, we examined the reaction of the acylsilane 1a (3.0 equiv.) and the imine 2a in the presence of Pd2(dba)3 (10 mol% [Pd]), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) (10 mol%) and CO (1.5 equiv.) in toluene at 110 °C, which afforded the expected β-lactam 3aa in 40% yield (entry 1, Table 1). Interestingly, this reaction proceeded even in the absence of CO to furnish 3aa in 48% yield (entry 2, Table 1). In this case, the phenylsilane 4, which we assume was formed by the decarbonylation of 1a (refs. 31,32,33), was also obtained in 30% yield. It therefore appears that palladium catalysis allows acylsilanes to serve not only as a carbene precursor but also as a source of CO, making this protocol operationally simple. The use of 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene (IPr*) substantially improved the yield of 3aa to 93% (entry 3, Table 1). No reaction occurred in the absence of a palladium catalyst, excluding the possibility that IPr* functions as an organocatalyst (entry 4, Table 1). This reaction proceeds in the absence of light, which excludes a mechanistic scenario involving the photo-induced isomerization of 1a to metal-free siloxycarbene (entry 5, Table 1)34,35 (for additional data for optimization, see Supplementary Tables 1–6).

Table 1 Pd-catalysed carbonylative annulation of acylsilane 1a and imine 2a
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This palladium-catalysed method allows the synthesis of a diverse range of complex β-lactams from readily available acylsilane and imine building blocks (Fig. 2). Imines bearing functional groups, such as methoxy (that is, 2b), trifluoromethyl (that is, 2c) on the aromatic rings successfully participated in this reaction with the corresponding β-lactams being formed. Imines with a bulky 2,6-xylyl group (that is, 2d) were also applicable to this reaction. The cyclic imine 2e served as a competent substrate, which allows access to complex polycyclic β-lactam skeleton (that is, 3ae). Not only aldimines but also ketimines (that is, 2f–2l) can be coupled successfully to form the corresponding β-lactams bearing contiguous quaternary stereocentres (that is, 3af–3al). Regarding the nitrogen substituent on the imine substrates, aryl, benzyl and amino (that is, 2i) groups were all compatible. Moreover, imines derived from cyclic ketones (that is, 2j and 2k) were transformed into spirocylic β-lactams that are otherwise synthesized with difficulty (that is, 3aj and 3ak). Imines bearing heteroaryl groups, such as thiophene (that is, 2l) and indole (that is, 2m), were also applicable to this reaction. With respect to the acylsilane component, various benzoylsilane derivatives, including those bearing methoxy (1b), fluoride (1c), ester (1d), trifluoromethyl (1e), cyano (1f) and 3,5-xylyl (1g) groups, readily participated in this reaction. Acylsilanes bearing a PhMe2Si group (that is, 1h) can also be used successfully to form the corresponding β-lactam. This β-lactam synthesis is also applicable to the synthesis of a scaffold found in antibiotics. For example, the reaction of acylsilane 1a with the cyclic imine 2n furnished the bicyclic β-lactam 3an, which possesses a molecular skeleton analogous to thienamycin. It should also be noted that a silyl group in the products obtained in this study can be removed by treatment with tetrabutylammonium fluoride to form the corresponding α-hydroxy-β-lactam derivative (for details, see Supplementary Methods).

Fig. 2: Scope of the palladium-catalysed synthesis of β-lactams by the reaction of acylsilanes and imines.
figure 2

Acylsilane (0.60 mmol), imine (0.20 mmol), Pd2(dba)3 (0.010 mmol), IPr* (0.020 mmol) and toluene (0.60 ml) in a sealed tube at 110 °C for 17 h. Isolated yields are shown. Ratios in parentheses are stereoisomer ratios, and the structure of the major isomer was determined by nuclear Overhauser effect spectroscopy. aThe structure of the major isomer was determined by X-ray crystallography (Supplementary Fig. 4). bAcylsilane (1.0 mmol) was used. cRun at 160 °C.

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Mechanistic studies

Some mechanistic studies were conducted to obtain insights into the reaction mechanism. The reaction of 1a with diethylamine, instead of an imine, under the standard catalytic condition was found to afford the amide 5 in 97% yield (Fig. 3a). This observation supports the intermediacy of siloxyketene, which could be captured by diethylamine to form 5. Second, the reaction of the 13C-labelled acylsilane 1a–13C and the imine 2g afforded the β-lactam 3ag–13C, in which C1 and C2 were both labelled, which is consistent with our mechanistic proposal that acylsilanes serve both as carbene and CO sources (Fig. 3b). Lastly, we successfully isolated a key siloxycarbene–palladium intermediate complex 6 by the reaction of Pd(CH2SiMe3)2(cod), IPr** (1.0 equiv.)36, and acylsilane 1i (Fig. 3c). The structure of 6 was unambiguously determined by X-ray crystallography. It should be noted that complex 6 represents a sought-after isolated palladium complex bearing an alkoxycarbene ligand.

Fig. 3: Mechanistic studies.
figure 3

a, Interception of a ketene intermediate with diethylamine. b, A reaction using 13C-labelled 1a. c, Isolation of a siloxycarbene–palladium 6. ORTEP drawing of 6 with thermal ellipsoids set at the 50% probability level is shown (for details, see Supplementary Fig. 5). THF, tetrahydrofuran.

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We also studied the mechanism for the generation of Pd–ketene complexes computationally using density functional theory (DFT) calculations at the ωB97XD/SDD-6-311+G*-SMD(toluene)//ωB97XD/LANL2DZ-6-31G*-SMD(toluene) level of theory (Fig. 4). Calculations were conducted using a model reaction of 1a with a Pd–IPr complex. It was revealed that oxidative addition of the C(acyl)–Si bond in 1a to the Pd–IPr complex proceeds through transition state TS1 with a relatively low energetic barrier (8.5 kcal mol−1), forming complex INT2. The silyl group INT2 subsequently migrates to the oxygen atom of the acyl ligand via the four-centred transition state TS2 with a feasible activation barrier (24.1 kcal mol−1), leading to carbene complex INT3. The coordination of CO, which is generated by a palladium-catalysed decarbonylation of 1a, stabilizes INT3 by 5.2 kcal mol−1 to form INT4. INT4 then undergoes CO insertion via TS3 with a viable activation barrier (17.2 kcal mol−1), generating the Pd–ketene complex INT5 (for an energy profile of the reaction of INT3 with 2a, see Supplementary Figs. 2 and 3). DFT calculations of the following [2 + 2] cycloaddition reactions with imines were reported for related Cr and Pd–ketene complexes37,38,39.

Fig. 4: DFT calculations.
figure 4

Computed energy profiles of the generation pathways from Pd–acylsilane complex INT1 to Pd–ketene complex INT5 at the ωB97XD/SDD-6-311+G*-SMD(toluene)//ωB97XD/LANL2DZ-6-31G*-SMD(toluene) level of theory (for details, see Supplementary Fig. 1).

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Conclusions

We report on the palladium-catalysed carbonylative cycloaddition of acylsilanes and imines, leading to the formation of densely functionalized β-lactam derivatives. Using this catalytic method, stoichiometric amounts of chromium–Fischer carbenes can be avoided. The key mechanistic feature of the reaction is the generation of a Fischer-type carbene complex from an acylsilane by a palladium/NHC catalyst, which was verified both experimentally and theoretically. The addition of external carbon monoxide, which is required for the formation of ketenes, is not necessary, because it is produced during the decarbonylation of acylsilanes, which is also catalysed by the same catalyst in the same reaction vessel. This operationally simple catalytic protocol allows for the rapid access to complex β-lactams from readily available building blocks. The system established in this study provides a reliable design principle in elusive Fischer-carbene catalysis. Further applications of this catalytic Fischer-carbene generation to other synthetic methods is currently ongoing in our laboratory.

Methods

A representative procedure for palladium-catalysed carbonylative cycloaddition of acylsilanes with imines

In a glovebox filled with nitrogen, Pd2(dba)3 (9.2 mg, 0.010 mmol), IPr* (18.3 mg, 0.020 mmol), acylsilane 1a (107.0 mg, 0.6 mmol) and imine 2a (37.3 mg, 0.21 mmol) were added to a 10-ml sample vial with a Teflon-sealed screwcap. Toluene (0.60 ml) was then added, and the vial was sealed with the cap. The vial was stirred at 110 °C for 17 h. After allowing the mixture to cool to room temperature, SiO2 (Silica Gel 60 (spherical) NH2) was added to the crude mixture, and the suspension was stirred at room temperature for 5 min. It was then filtered through a pad of SiO2 (Silica Gel 60 (spherical) NH2), and the pad was washed with EtOAc. The filtrate was concentrated in vacuo and purified by gel permeation chromatography (column: JAICEL-2HR-40, solvent: CHCl3, flow rate: 25 ml min−1) to give 3aa as a white solid (55.9 mg, 70% yield).