The reaction of a particularly electrophilic acyclic diaminocarbene with carbon monoxide: formation of β- and γ-lactams

1 Introduction

Acyclic diaminocarbenes (ADACs) [1], [2], [3], [4], [5], [6], [7], [8], [9] exhibit a much higher electrophilicity and nucleophilicity than NHCs and are superior even to cyclic (alkyl)(amino)carbenes (CAACs) [10], [11], [12], [13], [14] in this respect [15]. Owing to their ambiphilic profile, CAACs are suitable for the activation of fundamentally important small molecules like ammonia and carbon monoxide at room temperature or below [16], [17]. We recently found that ADACs, too, react with CO under very mild conditions [18], [19], [20], [21], which is perfectly plausible in view of the similar electronic profiles of CAACs and ADACs [15], [22]. The primary carbonylation product of an ADAC is the corresponding diaminoketene (R₂N)₂C=C=O, which is a transient species too unstable for isolation [23], [24], [25]. It is usually trapped through nucleophilic addition of unreacted ADAC, affording a betainic oxyallyl compound of the type [(R₂N)₂C]₂CO, which is a “2:1 product” of the ADAC with CO [20]. This process is hindered in sterically encumbered cases such as, for example, the iconic “Alder carbene” (iPr₂N)₂C [26], where a “1:1 product” is observed instead, because a retro-Wolff rearrangement of the diaminoketene takes place and the resulting transient (amido)(amino)carbene R₂N–C–C(O)NR₂ subsequently undergoes an intramolecular C–H insertion, affording a β-lactam derivative [20], [21]. We recently described the ADAC iPr₂N–C–TMP (TMP=2,2,6,6-tetramethylpiperidino), which is sterically significantly more encumbered and exhibits a substantially higher electrophilicity than (iPr₂N)₂C, or indeed any other ADAC known to date [27]. In view of these unique properties, we surmised that iPr₂N–C–TMP would react with CO in a way different from that of (iPr₂N)₂C. We here report that this indeed turned out to be the case.

2 Results and discussion

The ADAC iPr₂N–C–TMP (TMP=2,2,6,6-tetramethylpiperidino) was generated in situ as described before from the formamidinium salt [(iPr₂N)CH(TMP)][PF₆] (easily available in three steps from the secondary amines iPr₂NH and TMPH) and NaN(SiMe₃)₂ in THF at low temperatures [27]) and subsequently exposed to an atmospheric pressure of carbon monoxide. Standard work-up, including a purification step by column chromatography, afforded a brownish oil in moderate yield. An investigation by high-resolution electrospray mass spectrometry revealed that a “1:1 product” had been formed from CO and the ADAC. The IR spectrum of the oil showed two bands in the carbonyl region, located at 1675 and 1748 cm⁻¹. While the latter band is in the spectral region typical of β-lactams, the former one is consistent with a γ-lactam [28], indicating that the “1:1 product” in fact is a mixture of constitutional isomers. Attempts to achieve a separation of the isomers on a preparative scale by chromatography, including HPLC, unfortunately were not successful. Nevertheless, all isomers present in the “1:1 product” could be identified by single-crystal X-ray diffraction (XRD), which subsequently helped us to achieve at least a partial assignment of the signals in the complex ¹H and ¹³C NMR spectra recorded from the mixture of isomers. Prolonged storage of the oil at −40°C afforded crystals, which were used for an XRD study. The quality of the results of the structure determination was rather poor due to disorder. Consequently, a detailed discussion of the structure is not meaningful. However, the connectivities and stereochemical features were unequivocally established, revealing a bicyclic γ-lactam (Fig. 1), which was obtained as a racemic compound. The molecule contains two chiral centres, whose exocyclic substituents (iPr₂N and Me, respectively) are in a trans arrangement. This product will therefore be denoted as trans-1 in the following. The other diastereomer (cis-1) was obtained in protonated form more or less by serendipity. In the related case of an iPr₂N-substituted β-lactam, we had observed that treatment with HCl afforded a nicely crystalline hydrochloride, whose structure was subsequently determined by XRD [19]. This motivated us to layer a toluene solution of the brownish oil obtained as described above from iPr₂N–C–TMP and CO with a 2 m solution of HCl in diethyl ether. After several days, crystals of [cis-1H][FeCl₄] were obtained, which were suitable for an XRD study. The result is shown in Fig. 2. Again, a racemic compound was obtained. The presence of the tetrachloridoferrate(III) anion in the structure may be explained by the fact that the HCl solution had been transferred with a used, and hence very likely corroded, steel cannula in this experiment. Performing the protonation experiment on a preparative scale by adding a 2 m solution of HCl in diethyl ether with a glass pipette to a solution of the brownish oil in the same solvent resulted in essentially quantitative formation of the corresponding mixture of lactam hydrochlorides, from which the β-lactam hydrochloride [2H]Cl could be obtained by recrystallization from chloroform as single crystals suitable for XRD. The molecular structure of [2H]Cl is shown in Fig. 3.

Fig. 1:

Molecular structure of trans-1 in the crystal. Selected bond lengths (Å) and angles (deg): C1–C2 1.559(8), C1–N1 1.343(5), C2–N2 1.378(11), C1–O1 1.220(5); C2–C1–O1 123.5(4), N1–C1–C2 106.9(4), N1–C1–O1 128.0(4).

Fig. 2:

Molecular structure of [cis-1H][FeCl₄] and aggregation of its cations in the crystal. Selected bond lengths (Å) and angles (deg): C1–N1 1.334(4), C1–O1 1.231(4); N1–C1–O1 128.6(3), C1–O1···H 161.0.

Fig. 3:

Molecular structure of [2H]Cl in the crystal. Selected bond lengths (Å) and angles (deg): C1–C2 1.562(3), C1–N1 1.340(3), C1–O1 1.217(3), C2–N2 1.520(3); C2–C1–N1 91.3(2), C2–C1–O1 136.7(2), N1–C1–O1 131.6(2), N2–H···Cl1 159.8.

The structure of [2H]Cl is very similar to that of other hydrochlorides of amino-substituted β-lactams [18], [19]. Steric strain in the cation is indicated by the fact that N2 exhibits unusually long bonds to its carbon atoms, ranging from 1.520(3) to 1.572(3) Å (average value 1.554 Å). C–N bonds of ordinary trialkylammonium cations are substantially shorter than that. For example, Me₃NH⁺ exhibits C–N bond lengths ≤1.50 Å, whereas values of ca. 1.53 Å have been reported for sterically congested cases [29]. In the same vein, the C–N2–C angles, which range from 110.2(2) to 116.5(2)° (average value 114.3°), are expanded in comparison to Me₃NH⁺, which exhibits an average C–N–C angle of only 111.4° [29]. Steric strain appears to be slightly lower in the cation of the γ-lactam derivative [cis-1H][FeCl₄] than in the cation of the β-lactam derivative [2H]Cl, as is indicated by slightly shorter C–N2 bonds (average value 1.528 Å) and smaller C–N2–C angles (average value 113.7°) determined for the former compound. The chloride anion of [2H]Cl is hydrogen-bonded to the ammonium moiety of [2H]⁺ (indicated by a broken line in Fig. 3), as has been observed before for closely related compounds [18], [19]. In contrast to this, the tetrachloridoferrate(III) anion of [cis-1H][FeCl₄] is not involved in hydrogen bonding. Instead, the [cis-1H]⁺ cations are associated to dimers in the solid state, held together by hydrogen bonds between the amide and the ammonium units (indicated by broken lines in Fig. 2). This structural motif is not unprecedented for amides bearing a tertiary ammonium unit in α-position to the carbonyl unit [30].

Scheme 1 summarises the outcome of the carbonylation of iPr₂N–C–TMP and gives a plausible mechanistic explanation, which is based on our previous work with related bulky ADACs (vide supra) [18], [19], [21]. It is interesting that this carbonylation affords products belonging to two prominent classes of bioactive compounds. The β-lactams are one of the best known and intensively investigated ring systems due to both their utility as synthetic intermediates and their biological activity as antibiotics [31], [32], [33]. In the same vein, γ-lactams are at the heart of a number of medicinally and biologically important compounds, as well as a large collection of natural products, and the synthesis of functionalised γ-lactams is therefore attracting increased attention [34], [35]. Very recently, a palladium-catalysed route to functionalised γ-lactams using carbon monoxide and secondary amines as building blocks was published by Gaunt and co-workers [36]. It is of note that our synthesis of cis-1 and trans-1 is also based on CO and secondary amines (iPr₂NH and TMPH, vide supra), but does not require a catalyst.

Scheme 1:

Plausible formation mechanism for the lactams formed by carbonylation of in situ-generated iPr₂N–C–TMP. The primary carbonylation product is a diaminoketene, whose retro-Wolff rearrangement affords two different (amido)(amino)carbenes, each of which undergoes a final intramolecular C–H insertion step. The C–H bond that suffers the insertion is explicitly indicated. Each lactam was obtained as a racemate. Only one enantiomer is shown in each case.

3 Experimental section

All reactions involving air-sensitive compounds were performed in an inert atmosphere (argon or dinitrogen) by using standard Schlenk techniques or a conventional glovebox. Starting materials were procured from standard commercial sources and used as received. [(iPr₂N)CH(TMP)][PF₆] was synthesised according to the published procedure [27]. NMR spectra were recorded at ambient temperature with Varian NMRS-500 and MR-400 spectrometers operating at 500 and 400 MHz, respectively, for ¹H. High-resolution (HR) ESI mass spectra were obtained with a micrOTOF time-of-flight mass spectrometer (Bruker Daltonics, Bremen, Germany) using an Apollo™ “ion funnel” ESI source. Mass calibration was performed immediately prior to the measurement with ESI Tune Mix Standard (Agilent, Waldbronn, Germany). IR spectra were obtained with a Bruker ALPHA FT-IR spectrometer (ATR mode). Elemental analyses were carried out with a HEKAtech Euro EA-CHNS elemental analyser at the Institute of Chemistry, University of Kassel, Germany.

4 Supporting information

Figures S1 and S2, respectively, showing the ¹H and ¹³C NMR spectrum of the mixture of lactams obtained by carbonylation of iPr₂N–C–TMP are given as supplementary material available online (DOI: 10.1515/znb-2018-0255).