Evaluation of benzthiazolidine-based formamidinium salts for the synthesis of penem-type β-lactams by uncatalysed carbonylation of acyclic diaminocarbenes

1 Introduction

Acyclic diaminocarbenes (ADACs) are divalent carbon compounds of the type (R₂N)₂C [1], [2], [3], [4], [5], [6], [7], [8], [9], which are conveniently accessible starting from readily available secondary amines R₂NH. ADACs exhibit a much higher electrophilicity and nucleophilicity than N-heterocyclic carbenes (NHCs) and are superior even to cyclic (alkyl)(amino)carbenes (CAACs) [10], [11], [12], [13], [14] in this respect [15]. 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], [22], which is perfectly plausible in view of the similar ambiphilicities of CAACs and ADACs [15], [23]. The primary carbonylation product of an ADAC is the corresponding diaminoketene (R₂N)₂C=C=O, which is a transient species too unstable for isolation [24], [25], [26]. In sterically encumbered cases a retro-Wolff rearrangement of the diaminoketene takes place. The resulting transient (amido)(amino)carbene R₂N–C–C(O)NR₂ subsequently undergoes an intramolecular C–H insertion involving a substituent of its C(O)NR₂ moiety. If the R group contains an α-CH group, this process affords a β-lactam derivative [18], [19], [20], [22]. We have shown that monocyclic [18], [22], bicyclic [20] and spirocyclic β-lactams [19] with useful antibiotic properties are accessible by the carbonylation of sterically encumbered ADACs, which is the first metal-free method for the synthesis of β-lactams using CO as a building block. It complements the metal-catalysed one recently developed by Gaunt [27], [28], [29], [30], which also starts from secondary amines, but only allows the synthesis of mono- and disubstituted β-lactams, while our method provides facile access to trisubstituted derivatives.

The penicillins (penams) constitute a particularly important family of β-lactam antibiotics, whose structural core is a five-membered thiazolidine ring fused to the four-membered β-lactam ring. Due to increasing bacterial resistance to traditional β-lactam antibiotics, “non-classical” ones with tri- or polycyclic structures such as, for example the tricyclic trinems, have become the object of intense studies [31], [32], [33], [34], [35], [36], [37], [38]. This has motivated us to investigate the suitability of benzthiazolidine-based formamidinium salts for the synthesis of the hitherto extremely scarce benzo-fused tricyclic penems [39], [40] by uncatalysed ADAC carbonylation (Scheme 1). Our hope that the process selectively leads to tricyclic β-lactam derivatives was based on our previous observation of such a selectivity in the case of diisopropylamino-cis-2,6-dimethylpiperidinocarbene (iPr₂N)(PipMe₂)C, where only the cyclic PipMe₂ group undergoes the rearrangement and concomitant insertion [20].

Scheme 1:

Intended synthesis of penem-type benzo-fused tricyclic β-lactam derivatives. The formation of monocyclic β-lactam derivatives shown in grey was assumed to be less favoured.

2 Results and discussion

Our recent systematic study addressing the synthesis of precursors for sterically encumbered ADACs has shown that formamidinium salts of the type [(iPr₂N)CH(NRR’)][PF₆] are easily accessible by the reaction of the Vilsmeyer complex [iPr₂N=CHCl]Cl (formed by activation of the commercially available formamide iPr₂N–CHO with COCl₂ or POCl₃) with the corresponding secondary amine RR’NH and subsequent anion exchange using an aqueous solution of ammonium hexafluorophospate [41]. We selected the readily available 2-phenylbenzthiazolidine (Ph-BtzH) as the secondary amine for our present purposes and obtained the target formamidinium salt [(Ph-Btz)CH(NiPr₂)][PF₆] ([1aH][PF₆]) in 53% isolated yield (Scheme 2, top).

Scheme 2:

Synthesis of [1aH][PF₆] (top) and of the selenourea derivative 1aSe by trapping of the transient ACAD 1a generated in situ by deprotonation of the formamidinium unit of [1aH]⁺ (bottom).

¹H and ¹³C NMR spectroscopic data are in accord with the assumed structure of the cation, which was further corroborated by a single-crystal X-ray diffraction study (see below). Due to the presence of a chiral centre in close proximity, namely the Ph-substituted carbon atom of the five-membered heterocycle, the two isopropyl groups give rise to four CH₃ signals and two CH signals. The ¹H and ¹³C NMR signals due to the cationic N₂CH unit are located at δ=8.65 and 154.2 ppm, respectively, in acetone-d₆, which compares well with data obtained for closely related compounds such as, for example [(Ph₂N)CH(NiPr₂)][PF₆], where the corresponding signals were observed at δ=8.50 and 153.7 ppm in the same solvent. The nucleophilicity of the target ADAC (Ph-Btz)(NiPr₂)C (1a) can be judged from the ¹J_CH value determined for the N₂CH unit of its formamidinium cation. Ganter and Kunz have pointed out that such ¹J_CH coupling constants correlate inversely with the σ-donor strength, and hence the nucleophilicity, of the corresponding carbenes, since the σ-donor strength decreases with increasing s character of the σ orbital at the divalent carbon atom, and large ¹J_CH coupling constants reflect high s character of the carbon valence orbital involved in the C–H bond [42], [43]. ¹J_CH coupling constants determined for the protonated standard NHCs IMes and SIMes are 225 and 206 Hz, respectively [42], while the values determined for acyclic formamidinium cations are significantly lower (down to 183 Hz), indicating the comparatively high nucleophilicity of ADACs [19]. The value determined for [1aH][PF₆] is 192 Hz, which is identical to that of the closely related [(Ph₂N)CH(NiPr₂)][PF₆] as well as to that of [(Me₂N)₂CH]Cl, which is the precursor of the simplest persistent ADAC [44]. The electrophilicity of diaminocarbenes can be probed by a ⁷⁷Se NMR-spectroscopic investigation of the corresponding easily available selenourea derivatives. This well-established method [45] was introduced by Ganter et al. [46] and recently applied by us for a broad range of ADAC-derived selenoureas [41]. We found that the chemical shifts of the ⁷⁷Se NMR signals of these compounds in CDCl₃ lie in the range from 381 to 758 ppm. The signal of (iPr₂N)₂CSe, which is the selenourea derivative of the iconic “Alder carbene”, is located in the middle of this range. In the case of selenoureas derived from standard five-membered ring NHCs the chemical shifts lie between approximately −20 and 200 ppm [42], [46], [47], [48], in line with the comparatively low electrophilicity of these widely used carbenes. The selenourea derivative 1aSe was obtained in 75% isolated yield by treating [1aH][PF₆] with the sodium amide (Me₃Si)₂NNa in THF solution in the presence of grey selenium (Scheme 2, bottom). The ⁷⁷Se NMR signal of the product has a chemical shift (δ=595 ppm) in between those of (iPr₂N)₂CSe (δ=563 ppm) and (Ph₂N)(NiPr₂)CSe (δ=660 ppm).

Taken together, the NMR spectroscopic data just discussed indicate that 1a exhibits an ambiphilic profile typical of ADACs which readily react with CO under mild conditions. Consequently, [1aH][PF₆] was treated with (Me₃Si)₂NNa in THF solution under an atmospheric pressure of CO. However, the product (2), which was isolated after standard work-up, did not contain incorporated CO but was an isomer of ADAC 1a generated from 1aH⁺ by deprotonation. 2 was obtained in essentially identical yield (54%) when the deprotonation was performed under N₂ atmosphere. Its structure was unequivocally established by single-crystal X-ray diffraction (see below). Scheme 3 shows a plausible mechanism for the formation of the 2H-1,4-benzothiazine derivative 2. It is of note that the synthesis of 2H-1,4-thiazine derivatives is attracting increased attention due to the important biological functions of the products [49], [50], [51].

Scheme 3:

Plausible mechanism for the formation of 2.

The sequence involves initial deprotonation not at the cationic N₂CH unit, but at the neighbouring PhCH position of the heterocycle, which is plausible in view of the fact that the deprotonation of (benz-)thiazolidines at their 2-position has been described before for derivatives bearing electron-withdrawing OC(O)tBu (Boc) or CH=NtBu N-substituents [52], [53], [54]. In order to suppress the unwanted deprotonation at the 2-position of the heterocycle, iPr-BtzH and the spirocyclic (CH₂)₅-BtzH were utilised for the preparation of the corresponding formamidinium hexafluorophosphates [1bH][PF₆] and [1cH][PF₆] (Fig. 1).

Fig. 1:

Compounds [1bH][PF₆] and [1cH][PF₆].

In the former case we envisaged that the acidity of the iPrCH unit will be significantly lower than that of the PhCH unit present in [1aH][PF₆]. [1cH][PF₆] contains no such acidic hydrogen atom, because, being the spiro-atom, the carbon atom in the 2-position of the heterocycle is quaternary. The structures of both compounds have been determined by single-crystal X-ray diffraction (see below). Disappointingly, however, the deprotonation of [1bH][PF₆] or [1cH][PF₆] in the presence of elemental selenium as carbene trapping reagent did not furnish the corresponding selenourea derivative, but afforded only intractable material, whose very complex NMR spectra pointed to unspecific decomposition of the respective ADACs generated in the deprotonation step. Essentially identical results were obtained when the deprotonation was performed under CO atmosphere. The reactions were monitored by in situ FTIR spectroscopy, which gave no indication for the formation of carbonyl compounds.

We finally come to the solid-state structures of [1aH][PF₆] (Fig. 2), 1aSe (Fig. 3) and 2 (Fig. 4).

Fig. 2:

Molecular structure of [1aH][PF₆] in the crystal (ball-and-stick model). Selected bond lengths (Å) and angles (deg): C1–N1 1.331(2), C1–N2 1.306(2), C2–C9 1.519(3), C2–N1 1.475(2), C2–S1 1.8424(19), C3–S1 1.759(2), C4–N1 1.433(2); N1–C1–N2 129.6(2), C1–N1–C2 128.53(16), C1–N1–C4 120.30(16), C2–N1–C4 110.50(14), C2–S1–C3 89.47(9).

Fig. 3:

Molecular structure of 1aSe in the crystal (ball-and-stick model). Selected bond lengths (Å) and angles (deg): C1–N1 1.432(3), C1–N2 1.332(3), C1–Se1 1.829(2), C2–S1 1.753(2), C3–N1 1.411(3), C8–C9 1.505(3), C8–N1 1.484(2), C8–S1 1.835(2); N1–C1–N2 114.75(17), N1–C1–Se1 118.15(14), N2–C1–Se1 127.05(15), C1–N1–C3 117.49(16), C1–N1–C8 115.73(16), C3–N1–C8 111.10(16), C2–S1–C8 91.07(9).

Fig. 4:

Molecular structure of 2 in the crystal (ball-and-stick model). Selected bond lengths (Å) and angles (deg): C1–C2 1.528(4), C1–N2 1.420(3), C1–S1 1.874(3), C2–C9 1.488(4), C2–N1 1.275(4), C3–N1 1.428(4), C4–S1 1.748(3); C2–C1–S1 107.74(18), N2–C1–C2 111.0(2), N2–C1–S1 120.01(19), C2–N1–C3 121.7(3), C1–S1–C4 100.27(14). Compound 2 crystallises in the space group P2₁/c as a racemic compound. Only one enantiomer is shown.

The formamidinium unit of [1aH][PF₆] exhibits structural features typical for acyclic formamidinium salts [41]. The bond lengths in the N₂C unit [1.306(2) and 1.331(2) Å] and the N–C–N angle of 129.6(2)° are very similar to the values reported for the closely related [(Ph₂N)CH(NiPr₂)][PF₆] [1.305(3) and 1.345(3) Å, 131.5(2)°]. The dihedral angle between the N₂C plane of [1aH][PF₆] and the NC₂ plane of the NiPr₂ group is 9.7°, and that involving the heterocyclic amino group is 17.1°. These fairly small dihedral angles can be ascribed to π delocalisation in the N₂C unit, in line with trigonal-planar N atoms (sum of angles 359.3 and 360°) and C–N bond lengths in between the values typical of C(sp²)–N(sp²) single (1.41 Å) and double bonds (1.28 Å) [55]. In contrast, only the N atom of the iPr₂N unit of the selenourea derivative 1aSe is trigonal-planar (sum of angles 359.9°). The N atom of the heterocyclic amino group is significantly pyramidalised (sum of angles 344.3°), indicating that its lone pair is not involved in π delocalisation, which is supported by the large dihedral angle of 71.7° between the NC₂ plane of this amino group and of the N₂C unit and is also in line with the fact that the corresponding N–CSe bond length of 1.432(3) Å is typical for a C(sp²)–N(sp³) single bond. In contrast, the length of the corresponding bond involving the N atom of the iPr₂N unit is 1.332(3) Å, similar to the value determined for [1aH][PF₆]. The dihedral angle between the NC₂ plane of the iPr₂N and of the N₂C unit is only 2.6°. The C–Se bond length of 1.829(2) Å in 1aSe is unexceptional and lies in the close range between ca. 1.80 and 1.85 Å found for closely related compounds [41]. Such distances are in between the values typical of carbon−selenium single and double bonds, which has been rationalised in terms of a significant contribution of zwitterionic structures that feature single N₂C⁺−Se⁻ dative bonds [56], [57], [58]. Taken together, these structural data strongly suggest that the dominant resonance structure of 1aSe is iPr₂N⁺=C(Se⁻)–(Ph-Btz).

The six-membered heterocycle of 2 adopts a half-chair type conformation, as is commonly observed for 2H-1,4-benzothiazine derivatives [49], [59], [60], [61]. The most notable structural features of 2 are the two rather different C–S bond lengths of 1.748(3) and 1.874(3) Å. Considering the fact that the respective single bond covalent radii of C(sp³), C(sp²), and S are 0.76, 073, and 1.05 Å [62], respectively, it is evident that the difference between the two C–S bond lengths of ca. 0.12 Å is due more to an elongated C(sp³)–S than to a shortened C(sp²)–S bond, owing to a negative hyperconjugation of the type n_N→σ*_S−C involving the NiPr₂ group. This stereoelectronic effect can also explain the fact that the C–NiPr₂ bond of 2 (1.42 Å) is significantly shorter than C(sp³)–N(sp³) bonds in organic amines (1.46–1.48 Å) [63]. Substantially elongated carbon sigma bonds accompanied by shortened C–N bonds due to the negative hyperconjugative effect of neighbouring amino groups are not unprecedented [64]. Our hypothesis is more specifically supported by the fact that a structurally related amino-substituted benzothiopyran also exhibits an elongated C(sp³)–S bond (ca. 1.91 Å) [65], whereas no such elongation is found in 3-(4-methoxyphenyl)-2-(2-naphthylmethyl)-2H-3,4-benzothiazine, which contains an alkyl instead of the amino group and has a C(sp³)–S bond length of ca. 1.81 Å [59]. We have performed DFT calculations at the B97D/Def2-TZVP level to shed more light on the elongated C–S bond in 2. The natural bond orbital (NBO) analysis of the optimised gas phase structure gives a Wiberg Bond Index (WBI) of 0.88 for this C–S bond. Furthermore, the NBO analysis has shown that the lone pair of the nitrogen atom of the NiPr₂ group is involved in the C–NiPr₂ bond, since only 1.74 electrons are localised on the nitrogen atom and the WBI of this bond is slightly enhanced (1.06). These computational results are fully consistent with a negative hyperconjugation of the type n_N→σ*_S−C involving the NiPr₂ group as described above.

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. 2-Phenylbenzthiazolidine (Ph-BtzH) [66], its homologues iPr-BztH and (CH₂)₅-BtzH [67], and the Vilsmeyer complex [iPr₂N=CHCl]Cl [68] were synthesised by using adapted versions of the published procedures. NMR spectra were recorded at ambient temperature with Varian NMRS-500 and MR-400 spectrometers operating at 500 and 400 MHZ, respectively, for ¹H. ⁷⁷Se NMR spectra were recorded with a Varian NMRS-500 spectrometer. Neat dimethylselenide was used as external standard (δ=4 ppm) [69]. 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

Computational details are given as supplementary material.