Accessing Heteroannular Benzoxazole and Benzimidazole Scaffolds via Carbodiimides Using Azide–Isocyanide Cross-Coupling as Catalyzed by Mesoionic Singlet Palladium Carbene Complexes Derived from a Phenothiazine Moiety

Abstract

The coupling of aryl and aliphatic azides with isocyanides yielding carbodiimides (8–17) were efficiently catalyzed by well-defined structurally characterized trans-(MIC)PdI₂(L) [MIC = 1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene, L = NC₅H₅ (4), MesNC (5)], trans-(MIC)₂PdI₂ (6), and cis-(MIC)Pd(PPh₃)I₂ (7) type palladium complexes, which incidentally mark the first instances of the use of mesoionic singlet palladium carbene complexes for the said application. As observed from the product yields, the catalytic activity varied in the order 4 > 5 ∼ 6 > 7 for these complexes. A detailed mechanistic studies indicated that the catalysis proceeded via a palladium(0) (4a–7a) species. Using a representative palladium precatalyst (4), the azide–isocyanide coupling was successfully extended to synthesizing two different bioactive heteroannular benzoxazole (18–22) and benzimidazole (23–27) derivatives, thereby broadening the scope of the catalytic application.

Introduction

Carbodiimides have long evoked interest for over half a century now, primarily for their diverse range of applications varying from peptide synthesis to phosphorylation reactions to dehydration reactions.¹⁻³ Their biocompatibility and nontoxicity make them well-suited for peptide synthesis as cross-linkers providing “zero-length” amide linkages between carboxylic and amine groups.⁴ In organic synthesis, carbodiimides, belonging to the heterocumulene family of compounds and containing two adjacent C=N bonds, are also of sustained interest as they provide a unique opportunity for synthesizing N-heterocycles, which are known for their pharmaceutical properties.^5,6 The N-heterocycles constitute common fragments in marketed drugs and medicinal chemistry targets as a part of the drug discovery initiatives.¹ Hence, convenient access routes to these important carbodiimide class of compounds are in demand,⁷ and catalytically achieving that remains a challenging objective. Carbodiimides, with two adjacent C=N bonds, make synthons for N-heterocycles.^1,5

A common approach involves the decarboxylative coupling of isocyanates, leading to the elimination of CO₂.³ The method is primarily restricted to preparing symmetrical carbodiimides, as the selectivity between the homocoupled and heterocoupled products becomes an issue in coupling between different isocyanates. Notably, the syntheses of the more synthetically challenging unsymmetrical carbodiimides are obtained in a stoichiometric fashion by aza-Wittig reactions of phosphinimines with isocyanates⁸ and by the Sn-mediated metathesis of isocyanates and silyl amines.⁹ Under heterogeneous conditions, the catalytic oxidative coupling of primary amines to isocyanides using gold¹⁰ or PdCl₂/Ag₂O¹¹ produces carbodiimides.

However, an esoteric organometallic approach involving transition metal-mediated nitrene transfer in an azide–isocyanide coupling provides a more efficient atom economic approach to these carbodiimides.¹²⁻¹⁴ The appeal of this method resides in the easy and convenient synthetic access available for different azides, the simplicity of the process for preparing the symmetrical and unsymmetrical carbodiimides, and the generation of the environmentally benign dinitrogen as the only byproduct of the reaction.

Judicious exploitation of this method allows for the construction of a variety of bioactive heterocycles¹⁵ like the benzoxazoles known for their antibiotic, antifungal, antiviral, antitumor, antiulcer, antibacterial, anti-inflammatory, antitubercular, and analgesic properties^16,17 that rightfully constitute the core motif of a chiral nonsteroidal anti-inflammatory drug, flunoxaprofen.¹⁸ This approach also allows synthesis of other important N-heterocycles like the benzimidazoles having pharmaceutical and industrial applications.¹⁹

With our interest in exploring the potentials of the transition metal complexes of the heteroatom stabilized cyclic and acyclic singlet carbene ligands in homogeneous catalysis²⁰⁻²⁵ and in biomedical applications,²⁶ we study different singlet-carbene ligand classes covering the cyclic normal N-heterocyclic carbenes,²⁷ abnormal mesoionic carbenes^25,28 the acyclic diaminocarbenes^22,29 and the fused-cyclic ones of the imidazole,³⁰ benzimidazole,³¹ triazole,^23,24,32 oxazolidine,³³ bioxazoline,³⁴ and triazolooxazine³⁵ architectures. The mesoionic (MIC) carbenes, featuring less heteroatom stabilization than the more ubiquitous normal N-heterocyclic carbenes,³⁶ come with specific donors and reactivity properties but surprisingly remain less explored.³⁷ Because of the reasons mentioned above, we decided to study the catalytic utility of the transition metal complexes of the 1,2,3-triazole-derived mesoionic carbene in the azide–isocyanide coupling reaction for the synthesis of carbodiimides. In this regard, we decided to design a new type of the 1,2,3-triazole-derived mesoionic carbene ligand bearing phenothiazine moiety. Of late, phenothiazine has received attention for its organic light-emitting diodes (OLEDs), photovoltaic devices, data storage, sensors, and bioimaging applications but with no footprint in chemical catalysis.³⁸ Hence, we decided to pursue the potential of the phenothiazine-based 1,2,3-triazole-derived mesoionic carbene stabilized transition metal complexes in the azide–isocyanide coupling reaction.

Here, in the manuscript, we report a convenient synthetic route to various carbodiimide compounds (8–17) by the azide–isocyanide coupling mediated by palladium complexes (4–7) (Figure 1) of a new phenothiazine-based 1,2,3-triazole derived mesoionic carbene ligand. Further, we demonstrate their utility in synthesizing two bioactive heteroannular benzoxazole (18–22) and benzimidazole (23–27) derivatives.

Figure 1.

Synthesized phenothiazine-derived mesoionic singlet carbene complexes of palladium (4–7).

Results and Discussions

A new phenothiazine-derived mesoionic singlet carbene ligand namely, 1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene, was designed primarily for the reasons of exploring its utility in transition metal mediated homogeneous catalysis applications. This new class of phenothiazine functionalized 1,2,3-triazole derived N-heterocyclic carbene ligand was conveniently obtained from its triazolium iodide salt, 1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazolium iodide (3), by the alkylation reaction of 10-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-10H-phenothiazine (2) with MeI in ca. 99% yield (Scheme 1). The formation of 3 was confirmed by the observation of the characteristic (NCHC) resonance at δ ca. 9.52 ppm in the ¹H NMR spectrum and at δ ca. 143.1 in ¹³C{¹H} NMR spectrum (Supporting Information, Figures S13–S16). The corresponding NCH₃ resonance appeared at δ ca. 4.26 ppm in ¹H NMR, and at δ ca. 39.6 ppm in ¹³C{¹H} NMR. The Cu mediated click reaction between 10-(prop-2-yn-1-yl)-10H-phenothiazine (1) and benzyl azide yielded the desired phenothiazine functionalized 1,2,3-triazole derivative (2) in ca. 65% yield.³⁹

Scheme 1. Synthetic Routes to the Compounds (1–3) and the Phenothiazine-Derived Mesoionic Singlet Carbene Complexes of Palladium (4–7).

The 1,2,3-triazolium iodide salt (3) provided a convenient platform for accessing a large number of transition metal complexes. For example, the direct metalation reaction of (3) with PdCl₂ in pyridine, in the presence of K₂CO₃ as base yielded trans-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) (4) complex in 95% yield (Scheme 1). As expected, the o-NC₅H₅ resonance of the metal bound pyridine moiety appeared significantly downfield shifted at δ ca. 9.05 ppm as opposed to that of δ ca. 8.62 ppm for free pyridine in the ¹H NMR⁴⁰ (Supporting Information, Figures S20 and S21).

Furthermore, the characteristic Pd–C_carbene peak at δ ca. 139.0 ppm (Supporting Information, Figures S22–S23) in the ¹³C{¹H} NMR spectra of (4) is comparable to that observed for related trans-[1-Ph-3-Me-4-Ph-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) (δ ca.139.8 ppm),⁴¹trans-[{(S)-7-CH₂Ph-2-Me-6,7-dihydro-4H-[1,2,3]-triazolo[5,1-c][1,4]oxazin-3-ylidene}PdI₂(NC₅H₅) (δ ca.138.5 ppm)³⁵ and the other structurally characterized examples known in the literature (Supporting Information, Table S2).

As expected, the molecular structure of 4 (Figure 2 and Supporting Information, Table S1), as determined by the single crystal X-ray diffraction study, exhibited a nonplanar butterfly structure with the S and N heteroatoms occupying the 1,4 apical positions, while the two aromatic rings are pointed outward from the (2,3) and (5,6) positions of a boat confirmation, consistent with commonly observed conformation of a phenothiazine moiety.⁴² In agreement with the d⁸ configuration of a palladium(II) center, a square planar geometry was observed for 4 with the mesoionic 1,2,3-trizole based N-heterocyclic carbene ligand and the “‘throwaway’” pyridine moiety disposed at opposite ends of a near linear angle at the metal center [∠C(1)–Pd(1)–N(5) = 176.9(3)°] while two more iodine atoms occupied the other two trans positions [∠I(2)–Pd(1)–I(1) = 177.06(3)°].

Figure 2.

ORTEP diagram of 4 with thermal ellipsoids are shown at the 50% probability level. Selected bond lengths (Å) and angles (deg): Pd(1)–C(1) 1.981(5), Pd(1)–I(1) 2.6069(8), Pd(1)–I(2) 2.6104(8), Pd(1)–N(5) 2.105(7), I(2)–Pd(1)–I(1) 177.06(3), N(5)–Pd(1)–I(1) 90.34(19), N(5)–Pd(1)–I(2) 91.55(19), C(1)–Pd(1)–I(1) 88.0(2), C(1)–Pd(1)–I2 90.2(2), and C(1)–Pd(1)–N(5) 176.9(3).

The Pd–C_carbene bond distance of 1.981(8) Å in (4) compared well with the representative reported analogues, namely trans-[1-Ph-3-Me-4-Ph-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) [1.971(6) Å]⁴¹ and trans-{(S)-7-CH₂Ph-2-Me-6,7-dihydro-4H-[1,2,3]-triazolo[5,1-c][1,4]oxazin-3-ylidene}PdI₂(NC₅H₅) [1.974(9) Å].³⁵ (Supporting Information, Table S2).

A rare isocyanide bound palladium complex, trans-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]PdI₂(CN–Mes) (5), was prepared by the treatment of (4) with MesNC at ambient temperature in ca. 50% yield (Scheme 1). To the best of our knowledge, the palladium complex (5) represents the only reported example of a (MIC)PdI₂(CN–R) type complex of a mesoionic 1,2,3-triazole derived N-heterocyclic carbene. However, a handful of related analogues are known for benzimidazole^43,44 and indazole derived N-heterocyclic carbenes.⁴⁴ (Supporting Information, Table S3). Given the fact that all of these mixed carbene/isocyanide complexes were synthesized from a dimeric halide-bridged complex by treatment with the aliphatic and aromatic isocyanides,^43,44 the current method for the preparation of 5 offers a new way for accessing these type of mixed carbene/isocyanide complexes.

Of foremost importance to a mixed carbene/isocyanide themed precatalyst (5) is the metal bound isocyanide moiety. The successful coordination of MesNC to the Pd(II) center was evident from the ¹³C{¹H} NMR spectra for complex 5, where the Pd–CN signal appeared as a broad triplet at δ ca.138.7 ppm and was significantly downfield shifted (Δδ = ca. 14.6 ppm) in comparison to the free MesNC (δ ca.124.1 ppm) (Supporting info Figures S29 and S30). An analogue shift of (Δν) ca. 73 cm^–1 was observed for (ν(CN) = 2188 cm^–1) in IR spectroscopy with respect to the free MesNC (ν(CN) = 2115 cm^–1).⁴⁵

Single-crystal X-ray diffraction study revealed a square planar geometry for complex 5 (Figure 3 and Supporting Information, Table S1) analogous to that of complex 4. Quite interestingly, an elongation of the Pd–C_carbene bond length in 5 [2.002(5) Å] with respect to 4 [1.981(8) Å)], suggests a stronger trans-effect of the MesNC moiety in the former than the pyridine moiety in latter. Consistently, the Pd–CNMes bond length in (5) [1.970(5) Å] is significantly shorter than the sum of individual covalent radii of Pd and C_sp atoms [2.08 Å].⁴⁶ This observation is in agreement with a reported mixed indazole-carbene/isocyanide complex, trans-[1,2-Me₂-indazol-3-ylidene]PdI₂(CN–Xyl), [d/(Pd–C_carbene) = 2.002(5) Å and d/(Pd–CN) = 1.993(5) Å].⁴⁴ The benzimidazole derived analogues, trans-[1,3-Me₂-benzimidazol-2-ylidene]PdI₂(CN–Xyl)⁴⁴ [d/(Pd–C_carbene) = 1.996(3) Å and d/(Pd–CN) = 1.986(4) Å], trans-[1,3-Me₂-benzimidazol-2-ylidene]PdI₂(CN–Cy), [d/(Pd–C_carbene) = 1.986(4) Å and d/(Pd–CN) = 1.993(5) Å],⁴⁴ however, do not show such a profound trans-effect.

Figure 3.

ORTEP diagram of 5 with thermal ellipsoids are shown at the 50% probability level. Selected bond lengths (Å) and angles (deg): Pd(1)–C(1) 2.002(5), Pd(1)–I(1) 2.5892(5), Pd(1)–I(2) 2.6144(5), Pd(1)–C(24) 1.970(5), I(2)–Pd(1)–I(1) 178.11(2), C(24)–Pd(1)–I(1) 89.85(15), C(24)–Pd(1)–I(2) 90.14(15), C(1)–Pd(1)–I(1) 88.07(14), C(1)–Pd(1)–I2 92.07(14), and C(1)–Pd(1)–C(24) 175.6(2).

The complex (4), when treated with PPh₃, gave a mixed carbene/PPh₃ type complex cis-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ (7) in ca. 80% yield at ambient temperature (Scheme 1).

Quite interestingly, the ¹H, ¹³C{¹H} and ³¹P{¹H} NMR, all convincingly pointed at the existence of an equilibrium between cis-(7) and trans-(7′) species in solution at ambient temperature (Scheme 2 and Supporting Information, Figures S41–S45). Specifically, in the ¹H NMR spectrum, the NCH₃ resonance appeared at δ ca. 3.71 ppm for cis-(7) and at δ ca. 4.05 ppm for trans-(7′) in ca. 3.4:1 ratio. Indeed, in the variable temperature ¹H NMR experiment, the ratio of the NCH₃ resonances, one that appeared at δ ca. 3.71 ppm for cis-(7) and the other at δ ca. 4.05 ppm for trans-(7′), changed from ca. 3.4:1 at 25 °C to ca. 1:1 at 100 °C. (Supporting Information, Figures S219–S220). In the spin saturation ¹H NMR experiment, when the NCH₃ moiety of cis-(7) was irradiated at δ ca 3.71 ppm, the intensity of the NCH₃ moiety of trans-(7′) at δ ca. 4.05 ppm decreased and vice versa, thereby attesting to the equilibrium present between the two species in solution (Supporting Information, Figure S221).

Scheme 2. ¹H NMR Analysis Showing Equilibrium between cis-(7) and trans-(7′) in ca. 3.4:1 Ratio in Solution at Room Temperature.

Furthermore, diastereotopic resonances were observed for both the CH₂Ph and NCH₂ moieties in cis-(7), with a doublet pair observed at δ ca. 5.94 ppm and δ ca 5.07 ppm and at δ ca. 5.40 ppm and δ ca. 4.19 ppm, exhibiting geminal (²J_HH) coupling constants of 14 and 15 Hz respectively. In contrast, both the CH₂Ph and NCH₂ resonances were singlets at δ ca. 5.86 ppm and at δ ca. 5.43 ppm respectively for the trans-(7′) complex. The ¹³C{¹H} NMR of cis-(7) too showed the complete set of isomeric peaks due to the presence of the minor isomer trans-(7′) in solution. In the ³¹P{¹H} NMR, the Pd–P̲Ph₃ resonance at δ ca. 25.0 ppm was attributed to cis-(7), based on the reported examples, cis-[1-Et-3-Me-4-C₁₂H₉-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ (δ ca. 25.8 ppm)⁴⁷ and cis-[1-CH₂Ph-3-Me-4-Ph-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ (δ ca. 25.2 ppm).²⁵ (Supporting Information, Table S4), while the other upfield shifted Pd–P̲Ph₃ resonance at δ ca. 15.9 ppm was assigned to the trans-(7′), based on the related analogues, trans-[1-CH₂Ph-3-Et-4-C₆H₁₀OH-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂²⁵ (δ ca. 16.9 ppm) and trans-[1-CH₂Ph-3-Me-4-C₆H₁₀OH-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ (δ ca. 17.0 ppm).²⁵

The structural characterization using single crystal X-ray diffraction study revealed a cis complex (7) (Figure 4 and Supporting Information, Table S1), in which the mesoionic 1,2,3-trizole based N-heterocyclic carbene ligand and the PPh₃ moieties were in cis disposition around the square planar palladium(II) metal center [∠C(1)–Pd(1)–P(1) = 91.29(19)°] with the other two sites occupied by the iodine atoms [∠I(1)–Pd(1)–I(2) = 91.98(2)°]. Furthermore, the Pd–C_carbene [2.001(7) Å] and Pd–P_phosphine [2.2950(17) Å] bond distances in cis-(7) were in good agreement with other related complexes, namely cis-[1-Ph-3-Me-4-n-Bu-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ [d/(Pd–C_carbene) = 2.000(4) Å, d/(Pd–P_phosphine) = 2.2789(10) Å]⁴⁸ and cis-[1-CH₂Ph −3-Me-4-Ph-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ [d/(Pd–C_carbene) = 2.006(6) Å, d/(Pd–P_phosphine) = 2.2804(17) Å]²⁵ (Supporting Information, Table S4).

Figure 4.

ORTEP diagram of 7 with thermal ellipsoids are shown at the 50% probability level. Selected bond lengths (Å) and angles (deg): Pd(1)–C(1) 2.001(7), Pd(1)–I(1) 2.6381(6), Pd(1)–I(2) 2.6633(7), Pd(1)–P(1) 2.2950(17), I(1)–Pd(1)–I(2) 91.98(2), C(1)–Pd(1)–I(1) 87.18(19), C(1)–Pd(1)–I(2) 174.17(19), C(1)–Pd(1)–P(1) 91.29(19), P(1)–Pd(1)–I2 89.81(5), and P(1)–Pd(1)–I(1) 176.93(5).

The metalation of the triazolium iodide salt (3) with Pd(OAc)₂ quantitatively yielded the trans-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]₂PdI₂ complex (6) in 93% yield (Scheme 1). In this case too, two sets of resonances were observed in both the ¹H and ¹³C{¹H} NMR spectra signifying the presence of two conformers i.e. trans-anti and trans-syn (Supporting Information, Figures S34–S37). In the ¹H NMR spectrum, the sterically favored trans-anti isomer appeared in a ca. 1.7:1 ratio over the trans-syn conformer at 25 °C, which changed to ca. 1.5:1 at 50 °C. (Supporting Information, Figure S218).⁴⁹ In ¹³C{¹H} NMR spectra, two closely spaced Pd–C_carbene signals for the trans-anti and trans-syn conformers of 6 appeared at 156.7 and 156.4 ppm, respectively.

The complex (6) is among the few structurally characterized examples of the (MIC)₂PdI₂ type complexes supported over a 1,2,3 triazole-derived mesoionic N-heterocyclic carbene ligand known in the literature (Supporting Information, Table S5). The square planar complex (6) (Figure 5 and Supporting Information, Table S1) was surrounded by two mesoionic carbene units in [∠C(1)–Pd(1)–C(1ⁱ) = 180.0°], while two iodide atoms occupied the remaining two diametrically opposite sites [∠I(1)–Pd(1)–I(1ⁱ) = 180.0°]. In addition, the observed Pd–C_carbene bond distance of 2.030(4)Å and the Pd–I bond distance of 2.6107(3) Å were in close range to that reported for similar complexes, namely, trans-[1-Ph-3-Me-4-Ph-1,2,3-triazol-5-ylidene]₂PdI₂ [d/(Pd–C_carbene) = 2.026(6) Å, d/(Pd–I) = 2.6174(5) Å]⁵⁰ and trans-[1-Et-3-Me-4-Ph-1,2,3-triazol-5-ylidene]₂PdI₂ [d/(Pd–C_carbene) = 2.049(3) Å, d/(Pd–I) = 2.6181(3) Å].⁵¹ (Supporting Information, Table S5).

Figure 5.

ORTEP diagram of 6 with thermal ellipsoids are shown at the 50% probability level. Selected bond lengths (Å) and angles (deg): Pd(1)–C(1) 2.030(4), Pd(1)–I(1) 2.6107(3), and C(1)–Pd(1)–I(1) 88.66(10).

The palladium (4–7) complexes efficiently carried out the coupling of aryl and aliphatic azides with different isocyanides yielding carbodiimides in the presence of a base (Table 1, 2, 3 and Supporting Information, Table S6–S12). A series of optimization experiments on the representative pair of substrates, namely phenyl azide and benzyl isocyanide, with a representative precatalyst (4) provided the optimal catalysis conditions. As expected, the blank run performed without the precatalyst (4) and the base, produced no product for the aforementioned substrates (entry 1, Supporting Information, Table S12). The control run, performed only in the presence of the base K₂CO₃, too yielded no detectable product (entry 2, Supporting Information, Table S12). The control runs performed with the metal precursor Pd₂(dba)₃ gave ca. 41% product yield (entry 4, Supporting Information, Table S12) and that with 4 yielded no detectable product (entry 9, Supporting Information, Table S12). However, the same run when performed with Pd₂(dba)₃ and with 4 in the presence of the base K₂CO₃ produced N-[(benzylimino)methylene]aniline (8) in ca. 37% (entry 5, Supporting Information, Table S12) and ca. 88% (entry 10, Supporting Information, Table S12) yields respectively. Additional control runs involving the ligand precursor (3) in the presence of K₂CO₃ base showed no detectable product formation, thereby highlighting the significant influence played by the palladium (4–7) precatalysts in the azide–isocyanide coupling reaction (entry 3, Supporting Information, Table S12). Notably, the significant enhancement in the product yield by ca. 51% in case of complex 4, in comparison to Pd₂(dba)₃, highlights the favorable influence of the mesoionic 1,2,3-triazole derived N-heterocyclic carbene ligand in catalyzing the coupling of phenyl azide and benzyl isocyanide. The Hg drop experiment bore testimony toward the homogeneous nature of the catalysis as near equal yield of ca. 83% was found in the presence of mercury as opposed to 88% in absence of it (entries 10 and 11, Supporting Information, Table S12).

Table 1. Selected Results for Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4–7) Complexes Catalyzed Azide–Isocyanide Coupling Yielding Carbodiimides^a,b.

^aReaction conditions: azide (0.369 mmol), isocyanide (0.443 mmol), complex (4/5/6/7) (0.003 mmol, 1 mol %) and K₂CO₃ (1.10 mmol) in 5.0 mL of toluene at 50 °C for 12 h.

^bIsolated yields (%).

Table 2. Comparison of the Reaction Yield and Turnover Number (TON) Calculated with Respect to the Formation of N-[(Xylylimino)methylene]aniline in the Catalyzed Azide–Isocyanide Coupling Reaction of the Representative Phenyl Azide and 2,6-Dimethylphenyl Isocyanide Substrates as Catalyzed by 4–7 and other Transition Metal Complexes Known in the Literature.

Table 3. Selected Results for a Simple Practical Synthesis of a Variety of Benzoxazole Derivatives Using Azide–Isocyanide Coupling Catalyzed by a Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4) Complex^a,b.

^aReaction conditions: azide (0.369 mmol), isocyanide (0.443 mmol), complex 4 (0.003 mmol, 1 mol %), and K₂CO₃ (1.10 mmol) in 5.0 mL of toluene at 50 °C for 12 h.

^bIsolated yields (%).

Furthermore, the base variation study suggested K₂CO₃ (Supporting Information, Table S6) and the solvent variation study suggested toluene for optimal catalysis conditions (Supporting Information, Table S7). The variation of the molar ratio of the optimal base K₂CO₃ with the substrate phenyl azide produced highest yield at ca. 1:3 ratio (Supporting Information, Table S9). A catalysis reaction temperature of 50 °C (entry 2, Supporting Information, Table S8) and a catalyst loading of 1 mol % were found to be suitable based on the temperature dependence and the catalyst loading variation studies (entry 3, Supporting Information, Table S10).

The temperature dependence study with complex 4 showed that the product yield decreased with temperature, which can be attributed to the thermal decomposition of the azide moiety.⁵² Similar observation was made for the said azide–isocyanide coupling reaction mediated by Cr,¹³ as starting materials were decomposed, when the reaction mixture was heated beyond 60 °C.

In line with this investigation, the XPS analysis of the 4–7 complexes, before and after heating in toluene at 100 °C for 24 h, were performed. No trace of Pd leaching was observed in that process, and peaks corresponding to Pd(0) was also absent in the data. (Supporting Information, Figures S238–S246). Additionally, the temperature dependent ¹H NMR were also analyzed for complexes 4–7, and in this case too, no signature of decomposed peaks were found. (Supporting Information, Figures S216–S220). These experiments clearly showed that these (4–7) catalysts were stable during the catalysis conditions, and the decomposition of the azide substrates at the catalysis temperature was more dominant. It is worth noting that in long reaction time and under prolonged heating, carbodiimides tend to decompose or polymerize.^12,53

The time dependence study yielded 12 h to be the optimum reaction time as per the product yield (entry 4, Supporting Information, Table S11). Hence based on the aforementioned results, the catalysis conditions for the azide–isocyanide coupling that were chosen for the further substrate scope studies were at 1 mol % of the catalyst loading in the presence of the 3 equiv of K₂CO₃ in toluene at 50 °C for 12 h of the reaction time.

It is noteworthy to mention, all of the (4–7) complexes successfully carried out the azide–isocyanide coupling of different aryl azides ranging from phenyl azide to 4-methylphenyl azide, to 2-methoxyphenyl azide to 4-fluorophenyl azide to 3,5-bis(trifluoromethyl)phenyl azide to eventually an aliphatic azide, namely cyclohexyl azide with a host of isocyanides, namely, benzyl isocyanide, 4-methylphenyl isocyanide, 2,6-dimethylphenyl isocyanide, 2,4,6-trimethylphenyl isocyanide, and cyclohexyl isocyanide under the optimized catalysis conditions. Quite expectedly, with the increase in sterics, on going from 4-methylphenyl isocyanide to 2,6-dimethylphenyl isocyanide to 2,4,6-trimethylphenyl isocyanide, a steady decrease in the catalysis yield was observed for all the four (4–7) precatalysts when coupled with phenyl azide (entries 2–4, Table 1). Again, for the same isocyanide, i.e. benzyl isocyanide, the electron deficient 4-fluorophenyl azide and 3,5-bis(trifluoromethyl)phenyl azide performed consistently better than the corresponding electron rich 4-methylphenyl azide for all the (4-7) precatalysts (entries 7, 9, and 10, Table 1). Similar instances of higher reactivity of the electron deficient azides have been reported for an Fe catalyst and has been rationalized as a consequence of metal to azide π-back bonding that stabilizes the metal bound azide species.⁵⁴ For the coupling with cyclohexyl isocyanide higher yield was consistently observed with phenyl azide compared to its aliphatic counterpart cyclohexyl azide for all the four (4–7) precatalysts.

A careful scrutiny of the substrate scope study brings out an interesting trend of the catalyst reactivity observed along the line, 4 > 5 ∼ 6 > 7, thereby implying that the pyridine bound Pd complex (4) is the most effective, while the PPh₃ bound Pd complex (7) is the least effective of all the ten substrates studied for the azide–isocyanide coupling reaction. The other two precatalysts, i.e., the isocyanide bound Pd complex (5) and the bis-mesoionic 1,2,3-triazole based NHC complex (6), lie in between the highly active (4) and the least active (7) precatalysts, and are comparable to each other in terms of the catalysis product yield.

We are not aware of any other structurally characterized molecular palladium catalysts reported for the azide-iscocyanide coupling barring [Pd(PPh₃)₄].⁵⁵ Additionally, there exists only one other structurally characterized Ni(I) complex, namely (MesNCHCH₃CH₂CHCH₃NMes)Ni(2-picoline)¹⁴ for the azide–isocyanide coupling of the phenyl azide and 2,6-dimethylphenyl isocyanide pair of substrates, similar to that reported for our palladium complexes (4–7) (Table 2). Though the [Pd(PPh₃)₄]⁵⁵ complex reported a higher conversion of ca. 82% based on ¹H NMR at 5 h of reaction time at room temperature but at higher catalyst loading of 2.5 mol % in comparison to that of 1 mol % of the catalyst loading for our palladium complexes (4–7) showing moderate to good isolated yields of ca. 24–78% at 50 °C after 12 h of reaction time (Table 2). The Ni(I) complex, namely (MesNCHCH₃CH₂CHCH₃NMes)Ni(2-picoline)¹⁴ exhibited quantitative conversion by ¹H NMR at a longer reaction time of 17 h and also at a higher catalyst loading of 5 mol % at temperatures ranging from −35 °C to room temperature (Table 2). In light of these studies, the catalysis yields exhibited by our palladium (4–7) complexes are indeed promising and would usher further research into the area.

Moreover, in the absence of any prior report of Pd-NHC complex catalyzing the said reaction, a comparison with a benchmark PEPPSI catalyst namely, trans-[1,3-(2,6-(i-Pr)₂C₆H₃)₂-imidazol-2-ylidene]PdCl₂(NC₅H₅),⁵⁶ was made with the palladium (4–7) complexes under analogous catalysis conditions. Specifically, the benchmark PEPPSI complex, trans-[1,3-(2,6-(i-Pr)₂C₆H₃)₂-imidazol-2-ylidene]PdCl₂(NC₅H₅) was synthesized according to the literature procedure,⁵⁶ and when used to carry out the same catalysis, (entry 7, Supporting Information, Table S12) exhibited inferior performance in comparison to our (4–7) catalysts. Another triazolylidene based palladium complex trans-[1-Ph-3-Me-4-CH₂Ph-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅),²⁵ having a phenyl group rather phenothiazine, too exhibited inferior activity than the (4–7) catalysts (entry 8, Supporting Information, Table S12). The study further highlights the significance of these MIC based (4–7) catalysts in the azide–isocyanide coupling reaction.

A unified mechanism involving redox palladium (0/II) oxidation states have been proposed for the (4–7) complexes catalyzing the azide–isocyanide coupling in case of the two representative substrates, phenyl azide and benzyl isocyanide, (Scheme 3 and Supporting Information, Scheme S1 and Figures 6, 7, 8, and S222–S237).⁵⁵ The proposed catalysis initiates with the formation of the Pd(0) species 4a, 5a, and 7a (Scheme 3) and 6a (Supporting Information, Scheme S1) from the respective Pd(II) (4–7) complexes with the reduction of the metal center occurring in the presence of the base K₂CO₃.⁵⁷ With 3 equiv of K₂CO₃, the catalysis yield was found to be the maximum according to the base and base equivalence variation studies (Supporting Information, Tables S8 and S11), which can be attributed to the fact that K₂CO₃, being a weak inorganic base, has less solubility in an organic solvent like toluene.⁵⁸ Quite significantly mass evidence are consistent with the proposed 4a (Figure 6 and Supporting Information, Figure S222), 7a (Supporting Information, Figured S230 and S231) and 6a (Supporting Information, Figures S234 and S235). Upon reaction with phenyl azide, the Pd bound nitrene species, 4b, 5b, and 7b (Scheme 3) and 6b (Supporting Information, Scheme S1) are formed with the elimination of N₂, and of which 4b (Figure 7 and Supporting Information, Figure S223) 5b (Supporting Information, Figures S226 and S227) have been observed by mass spectrometry. Subsequently, the insertion of benzyl isocyanide into the Pd–nitrene species 4b, 5b, and 7b (Scheme 3) yields a common intermediate (C) (Figure 8 and Supporting Information, Figures S224, S225, S228, S229, S232, and S233), while 6b generates the intermediate 6c (Supporting Information, Scheme S1 and Figures S236 and S237), and both C and 6c have also been observed by mass spectrometry. Finally, a reductive elimination step regenerates the Pd(0) species 4a, 5a, and 7a (Scheme 3) and 6a (Supporting Information, Scheme S1) along with the elimination of the free carbodiimide product (8).

Scheme 3. Proposed Mechanism Showing the Intermediates 4a,b, 5a,b, 6a,b, and C for the Azide–Isocyanide Coupling as Catalyzed by Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4, 5, 7) Complexes for the Representative Substrates, Namely Phenyl Azide and Benzyl Isocyanide.

Figure 6.

Expanded ESI-MS data consistent with the proposed Pd (0) species [1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]Pd(NC₅H₅) (4a), [M-H]⁻ detected in the reaction mixture of K₂CO₃, 3 mmol and 1 mol % of catalyst (4) in 5.0 mL of toluene heated at 50 °C for 30 min [(a) experimental and (b) simulated pattern of ESI-MS data].

Figure 7.

Expanded ESI-MS data consistent with the proposed Pd bound nitrene species [1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]Pd(=NC₆H₅)(NC₅H₅) (4b), [M + H]⁺ detected in the reaction mixture of phenyl azide, 1 mmol of K₂CO₃, 3 mmol, 1 mol % of catalyst (4), 5.0 mL of toluene at 50 °C for 1 h [(a) experimental and (b) simulated pattern of ESI-MS data].

Figure 8.

Expanded ESI-MS data consistent with the proposed species [1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]Pd[η²-(Ph)N=C(NCH₂Ph)] (C), [M]⁺ detected in the reaction mixture of phenyl azide, 1 mmol of benzyl isocyanide, 1.2 mmol of K₂CO₃, 3 mmol, 1 mol % of catalyst (4), 5.0 mL of toluene at 50 °C for 1.5 h [(a) experimental and (b) simulated pattern of ESI-MS data].

In this regard, it is noteworthy that ESI-MS studies⁵⁹ have been routinely used for screening short-lived, low concentration intermediate species of several homogeneous metal-catalyzed transformations.⁶⁰ However, since the information about the charged state of a metal, if obtained from the ESI-MS technique, remains inconclusive,⁶¹ and so such efforts demands further validation by other experimental techniques. In the present study such validation regarding the oxidation state of the metal center has been obtained using X-ray photoelectron spectroscopy as discussed below.

Additional corroboration of the proposed mechanism came from the X-ray photoelectron spectroscopy studies. In particular, the X-ray photoelectron spectroscopy (XPS) analysis of complexes 4–7 showed the presence of palladium, iodine, nitrogen, sulfur, and carbon in the precatalysts. As expected for the molecular complexes, the binding energies of Pd confirm its +2 oxidation state.⁶² A comparative XPS analysis of complexes 4–7 after heating in toluene at 100 °C for 24 h showed that the characteristic core level peaks of Pd 3d, I 3d, N 1s, S 2p, and C 1s are at the same binding energies as for the molecular complexes (Figure 9 and see Supporting Information, Table S13 and Figures S238–S246). The 3d core-level palladium of complex 4 was fitted with two main peaks, the peak for Pd 3d_5/2 at 341.7 eV and for Pd 3d_3/2 at 336.4 eV, which were assignable to the Pd(II) oxidation state.^62,63 To characterize the intermediate species generated during the azide–isocyanide coupling reaction X-ray photoelectron spectroscopy (XPS) study was inspected of the reaction mixture using phenyl azide, benzyl isocyanide and complex 4. Two different new peaks at 335.5 and 340.9 eV, attributed to Pd 3d_5/2 and Pd 3d_3/2 peaks of Pd(0) species, appeared in the analysis.^62,63 These peaks confirmed that both Pd(II) and Pd(0) species were involved during the catalytic cycle.

Figure 9.

XPS analysis of the 3d core level peaks of level of Pd 3d: Pd(II) (black), Pd(0) (pink), (a) precatalyst 4, and (b) precatalyst 4 after treatment with PhN₃, PhCH₂NC, and K₂CO₃ for 12 h in 5 mL of toluene at 50 °C.

As part of our ongoing efforts to synthesize bioactive heterocycles in a tandem fashion,^21,22,24 the azide–isocyanide cross-coupling was extended to accessing benzoxazole motifs from the reaction of o-functionalized aryl azides with different isocyanides. Specifically, the representative catalyst (4) successfully catalyzed the coupling and the cyclization sequence steps producing the 2-aminobenzoxazole derivatives (18–22) from the reaction of 2-azido alcohol and R–NC [R = Cy (18), 2,6-Me₂C₆H₃ (19), t-Bu (20), 2,4,6-Me₃C₆H₂ (21), CH₂C₆H₅ (22)] under optimal catalysis conditions in moderate to excellent yields of 54–89% (Table 3). It is needless to mention that the benzoxazole rings are important for their antimicrobial, anticonvulsant, anti-inflammatory and anticancer properties and are also studied for their DNA topoisomerase inhibitor and cholesterol ester transfer protein (CETP) inhibitor activities.^16,64

A similar coupling/cyclization sequence were extended for synthesizing various bioactive 2-substituted benzimidazoles.⁶⁵ In particular, the representative precatalyst (4) coupled the 2-halidophenyl azide with benzyl and cyclohexyl isocyanides yielding the corresponding o-haloarylcarbodiimides, followed by a cascade cyclization process in the presence of another Cu(I) catalyst in one pot and without the need for isolation of the intermediate to give the N-substituted 2-heterobenzimidazoles derivatives (23–27) in good yields using different N-heterocycles as nucleophiles (Table 4).

Table 4. Selected Results for a Simple Practical Synthesis of a Variety of Benzimidazole Derivatives Using Azide–Isocyanide Coupling Catalyzed by a Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4) Complex^a,b.

^aReaction conditions: azide (0.369 mmol), isocyanide (0.443 mmol), complex 4 (0.003 mmol, 1 mol %), and K₂CO₃ (1.10 mmol) in 5.0 mL of toluene at 50 °C for 12 h. Reaction mixture was cooled to room temperature and then CuI (0.100 mmol, 10 mol %), 1,10-phenanthroline (0.200 mmol, 20 mol %), Cs₂CO₃ (2.00 mmol), and N-heterocycle (1.10 mmol) were added to it and heated at 80 °C for 20 h.

^bIsolated yields (%).

Conclusion

In conclusion, several late transition metal complexes of palladium (4–7) were stabilized over a new class of phenothiazine derived mesoionic 1,2,3-triazole based carbene (MIC) ligand (3), thereby highlighting the versatility of this kind of MIC ligand for synthesizing different metal complexes. Significantly enough, the mixed carbene/isocyanide complex (5) represents the only structurally characterized example known until date of a (MIC)PdI₂(CN–R) type complex, supported over a mesoionic 1,2,3-triazole derived carbene. The palladium (4–7) complexes efficiently catalyzed the azide–isocyanide coupling reaction yielding various symmetrical and unsymmetrical carbodiimides (8–17). More importantly, the (MIC)PdI₂(NC₅H₅) type complex (4) beats out all other palladium complexes (5–7) in terms of catalysis performance, while the PPh₃ bound cis-(MIC)Pd(PPh₃)I₂ type complex (7) was found to be the least active one. The remaining two complexes, i.e., the mixed carbene/isocyanide (MIC)PdI₂(CN–R) type complex (5) and the trans–(MIC)₂PdI₂ type complex (6) exhibited comparable catalytic activities. The mechanistic study performed on two representative substrates, i.e. the phenyl azide and benzyl isocyanide revealed that the catalysis proceeds through the formation of palladium(0) species of the type (MIC)Pd(L) [L = NC₅H₅, MesNC, MIC, PPh₃] and the palldium bound nitrene species (MIC)]Pd(=NC₆H₅)(L) [L = NC₅H₅, MesNC, PPh₃, MIC], and of which the following species (4a, 6a, 7a, 4b, and 5b) have been characterized by mass spectrometry. The scope of the azide–isocyanide coupling was successfully extended by demonstrating its application in the formation of different derivatives of two bioactive heteroannular ring systems namely, 2-aminobenzoxazole (18–22) and the N-substituted 2-heterobenzimidazole (23–27). As the 4–7 complexes represent a rare class of well-defined palladium based molecular catalyst for the azide–isocyanide coupling reaction yielding various carbodiimide compounds, the study will provide further impetus to the development of the area.

Experimental Section

General Procedures

All manipulations were carried out using standard Schlenk techniques. Solvents were purified and degassed by standard procedures. Benzyl bromide, sodium azide, and methyl iodide were purchased from Spectrochem Chemicals and phenothiazine and propargyl bromide were purchased from Sigma-Aldrich Chemicals and used without any further purification. ¹H NMR and ¹³C{¹H} NMR spectra were recorded on Bruker 400 MHz and Bruker 500 MHz NMR spectrometer. ¹H NMR peaks are labeled as singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), doublet of triplets (dt), triplets of doublets (td), doublet of triplets of triplets (dtd), and multiplet (m). Variable temperature dependent ¹H NMR for complexes 4–6 were recorded on a JEOL ECZR Series 600 MHz NMR spectrometer. Variable Temperature dependent ¹H NMR and spin saturation transfer (SST) ¹H NMR for complex 7 were recorded on a Bruker 400 MHz spectrometer. The 10-(prop-2-yn-1-yl)-10H-phenothiazine was synthesized by modification of procedures reported in literature.⁶⁶ The benchmark PEPPSI complex [trans-[1,3-(2,6-(i-Pr)₂C₆H₃)₂-imidazol-2-ylidene]PdCl₂(NC₅H₅),] was made according to the literature procedure.⁵⁶ High-resolution mass spectrometry measurements were done on a Micromass Q–Tof spectrometer and a Bruker maxis impact spectrometer. Infrared spectra were recorded on a PerkinElmer Spectrum One FT-IR spectrometer. Elemental Analysis was carried out on Thermo Quest FLASH 1112 SERIES (CHNS) Elemental Analyzer. X-ray photoelectron spectra were acquired on ULVAC-PHI/PHI 5000 VersaProbe-II spectrometer with a monochromatic Al Kα X-ray source (1486.6 eV) using a pass energy of 58.7 eV. X-ray diffraction data were collected for compounds (4–7) on a Bruker D8 QUEST single crystal diffractometer with Mo Ka (k = 0.71073 Å) radiation. The Bruker D8 QUEST single-crystal X-ray diffractometer were equipped with an Oxford liquid nitrogen cryostream. Crystals were mounted on a nylon loop with paraffin oil. The structures were solved via direct methods using SHELXT and refined via the full matrix least-squares method with SHELXL-2018/3, refining on F².⁶⁷ Crystal data collection and refinement parameters were summarized in Supporting Information, Table S1. CCDC-2041824 (for 4), CCDC-2060553 (for 5), CCDC-2123529 (for 6), and CCDC-2069000 (for 7), contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data center via www.ccdc.cam.ac.uk/data_request/cif.

Synthesis of 10-(Prop-2-yn-1-yl)-10H-phenothiazine (1)⁶⁶

A mixture of phenothiazine (5.00 g, 25.0 mmol) and Na₂CO₃ (3.98 g, 37.5 mmol) in ca. 50 mL of anhydrous toluene was stirred at room temperature for 30 min, followed by the dropwise addition of propargyl bromide (80 wt % in toluene, 5.57 g, 37.5 mmol). The reaction mixture was refluxed for 24 h, after which it was evaporated invacuo. The resultant residue was dissolved in ca. 100 mL of CH₂Cl₂, filtered and washed with water (ca. 2 × 50 mL). The collected organic layer was dried over anhydrous Na₂SO₄ and evaporated invacuo. The crude product was further purified by column chromatography using silica gel as the stationary phase and by elution with petroleum ether to obtain a white solid (1) (2.12 g, 35%). ¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.22 (dd, 2H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 7.18 (td, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 7.13 (dd, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 6.95 (td, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 4.52 (d, 2H, ⁴J_HH = 2 Hz, NCH₂C≡CH), 2.46 (t, 1H, ⁴J_HH = 2 Hz, NCH₂C≡CH). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 144.1 (C₁₂H₈NS), 127.5 (C₁₂H₈NS), 127.1 (C₁₂H₈NS), 123.4 (C₁₂H₈NS), 123.0 (C₁₂H₈NS), 114.8 (C₁₂H₈NS), 79.3 (NCH₂C≡CH), 74.5 (NCH₂C≡CH), 38.5 (NCH₂CCH). HRMS (ESI): calcd for [C₁₅H₁₁NS + K]⁺, 276.0244; found, 276.0239.

Synthesis of 10-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-10H-phenothiazine (2)

10-(Prop-2-yn-1-yl)-10H-phenothiazine (1) (0.478 g, 2.01 mmol), benzyl azide (0.322 g, 2.41 mmol), CuSO₄·5H₂O (0.604 g, 2.41 mmol), and sodium ascorbate (0.479 g, 2.41 mmol) were mixed together in 10 mL of DMF and refluxed for 24 h. The reaction mixture was diluted with ca. 50 mL of CH₂Cl₂ and ca. 150 mL of water and stirred vigorously at room temperature for 30 min. Subsequent separation of the organic layer, followed by repeated washing with water (ca. 3 × 100 mL), drying over anhydrous Na₂SO₄, and finally evaporating the volatiles invacuo gave the crude product, which was further purified by column chromatography using silica gel as the stationary phase and by elution with CH₂Cl₂ to get a white solid (2) (0.485 g, 65%). ¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.21–7.17 (m, 4H, C₂HN₃ and CH₂C₆H₅), 7.01 (dd, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 7.00–6.99 (m, 2H, CH₂C₆H₅), 6.95 (td, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 6.80 (td, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 6.67 (dd, 2H, ³J_HH = 7 Hz, ⁴J_HH = 1 Hz, C₁₂H₈NS), 5.36 (s, 2H, CH₂C₆H₅), 5.11 (s, 2H, NCH₂). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 145.3 (C₁₂H₈NS), 144.2 (C₂HN₃), 134.6 (CH₂C₆H₅), 129.0 (CH₂C₆H₅), 128.5 (CH₂C₆H₅), 127.5 (C₁₂H₈NS), 127.3 (CH₂C₆H₅), 127.1 (C₁₂H₈NS), 124.0 (C₁₂H₈NS), 122.8 (C₁₂H₈NS), 122.5 (C₂HN₃), 115.3 (C₁₂H₈NS), 54.1 (NCH₂), 45.0 (CH₂C₆H₅). IR data (cm^–1) KBr pellet: 3445 (m), 3121 (m), 3062 (m), 2946 (m), 1571 (m), 1495 (s), 1440 (s), 1357 (s), 1286 (s), 1251 (s), 1210 (s), 1122 (s), 1050 (s), 857 (s), 749 (s), 718 (s), 643 (s), 616 (s). HRMS (ESI): calcd for [C₂₂H₁₈N₄S + H]⁺, 371.1325; found, 371.1323. Anal. Calcd for C₂₂H₁₈N₄S: C, 71.33; H, 4.90; N, 15.12; S, 8.65. Found: C, 71.21; H, 4.58; N, 14.80; S, 8.93%.

Synthesis of 1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazolium Iodide (3)

10-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-10H-phenothiazine (2) (0.400 g, 1.07 mmol), and MeI (1.53 g, 10.8 mmol) were mixed in 10 mL of CH₃CN and refluxed for 24 h. The reaction mixture was then cooled to room temperature and all the volatiles were evaporated in vaccuo. The crude product thus obtained was further purified through column chromatography using silica gel as the stationary phase and by elution with CHCl₃/MeOH (95:5 v/v) mixture to get the product as a yellow solid (3) (0.548 g, 99%). ¹H NMR (CDCl₃, 500 MHz, 25 °C): δ 9.52 (s, 1H, NCHC of C₂HN₃), 7.35–7.27 (m, 5H, C₁₂H₈NS and CH₂C₆H₅), 7.14 (t, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.08 (d, 4H, ³J_HH = 8 Hz, C₁₂H₈NS), 6.89 (t, 2H, ³J_HH = 8 Hz, C₁₂H₈NS), 5.73 (s, 2H, CH₂C₆H₅), 5.57 (s, 2H, NCH₂), 4.26 (s, 3H, NCH₃). ¹³C{¹H} NMR (CDCl₃, 125 MHz, 25 °C): δ 143.1 (C₂HN₃), 139.8 (C₁₂H₈NS), 131.6 (C₂HN₃), 131.1 (CH₂C₆H₅), 129.8 (CH₂C₆H₅), 129.4 (CH₂C₆H₅), 129.1 (CH₂C₆H₅), 128.2 (C₁₂H₈NS), 127.8 (C₁₂H₈NS), 125.7 (C₁₂H₈NS), 124.0 (C₁₂H₈NS), 116.7 (C₁₂H₈NS), 57.5 (NCH₂), 41.8 (CH₂C₆H₅), 39.6 (NCH₃). IR data (cm^–1) KBr pellet: 3433 (m), 3061 (w), 2924 (w), 2851 (w), 1589 (s), 1572 (w), 1485 (w), 1461 (s), 1352 (m), 1320 (m), 1285 (m), 1254 (m), 1224 (m), 1160 (w), 1079 (w), 933 (m), 854 (m), 754 (s), 643 (s), 572 (w), 512 (w), 473 (w). HRMS (ESI): calcd for [C₂₃H₂₁N₄S]⁺, 385.1481; found, 385.1482. Anal. Calcd for C₂₃H₂₁N₄IS: C, 53.91; H, 4.13; N, 10.93; S, 6.26. Found: C, 53.94; H, 4.42; N, 10.54; S, 6.62%.

Synthesis of trans-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) (4)

A mixture of 1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazolium iodide (3) (0.250 g, 0.487 mmol), PdCl₂ (0.086 g, 0.487 mmol), K₂CO₃ (0.337 g, 2.43 mmol), and NaI (0.365 g, 2.43 mmol) was refluxed in pyridine (5 mL, 63.0 mmol) for 16 h. The reaction mixture was cooled to room temperature, diluted with CHCl₃ (ca. 50 mL), filtered and subsequently washed with saturated aqueous CuSO₄ solution (ca. 3 × 50 mL) and water (ca. 100 mL). The organic layer was separated and dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum to give a sticky, brown residue. The residue thus obtained was further triturated using hexane and EtOAc to give the product (4) as a yellow solid (0.381 g, 95%). ¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 9.05 (d, 2H, ³J_HH = 5 Hz, NC₅H₅), 7.75 (t, 1H, ³J_HH = 7 Hz, NC₅H₅), 7.63 (dd, 2H, ³J_HH = 7 Hz, ⁴J_HH = 2 Hz, C₁₂H₈NS), 7.44–7.39 (m, 3H, CH₂C₆H₅), 7.35 (t, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.31–7.29 (m, 4H, C₁₂H₈NS and NC₅H₅), 7.22 (d, 2H, ³J_HH = 7 Hz, ⁴J_HH = 2 Hz, C₁₂H₈NS), 7.03–6.99 (m, 2H, C₁₂H₈NS), 5.96 (s, 2H, CH₂C₆H₅), 5.54 (s, 2H, NCH₂), 4.00 (s, 3H, NCH₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 153.7 (NC₅H₅), 143.6 (C₁₂H₈NS), 139.0 (Pd-C), 137.3 (NC₅H₅), 134.8 (CH₂C₆H₅), 133.3 (C₂N₃), 129.8 (CH₂C₆H₅), 128.6 (CH₂C₆H₅), 128.5 (CH₂C₆H₅), 128.2 (C₁₂H₈NS), 127.4 (C₁₂H₈NS), 125.0 (C₁₂H₈NS), 124.2 (C₁₂H₈NS), 123.4 (NC₅H₅), 117.0 (C₁₂H₈NS), 59.5 (NCH₂), 45.3 (CH₂C₆H₅), 37.8 (NCH₃). IR data (cm^–1) KBr pellet: 3439 (s), 3031 (w), 2954 (w), 2922 (w), 2851 (w), 2602 (w), 1732 (w), 1602 (w), 1457 (s), 1446 (s), 1364 (m), 1325 (m), 1258 (m), 1225 (m), 1213 (m), 1153 (w), 1129 (w), 1105 (w), 1070 (w), 956 (s), 865 (m), 753 (s), 618 (w), 580 (w), 498 (w). HRMS (ESI): calcd for [C₂₈H₂₅N₅I₂PdS–C₅H₅N–I]⁺, 616.9483; found, 616.9487. Anal. Calcd for C₂₈H₂₅N₅I₂PdS: C, 40.82; H, 3.06; N, 8.50; S, 3.89. Found: C, 40.59; H, 3.06; N, 7.95; S, 3.30%.

Synthesis of trans-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]PdI₂(CN–Mes) (5)

A mixture of [1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) (4) (0.340 g, 0.413 mmol) and MesNC (0.090 g, 0.619 mmol) was dissolved in a mixed solvent medium of dry toluene (ca. 5 mL) and dry THF (ca. 5 mL) and stirred at room temperature for 24 h. The solvent was evaporated and the crude product thus obtained was further purified by column chromatography using silica gel as stationary phase and by elution with petroleum ether/ethyl acetate (90:10 v/v) mixture to get a yellow solid (5) (0.161 g, 50%). ¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.56 (d, 2H, ³J_HH = 7 Hz, C₁₂H₈NS), 7.39–7.35 (m, 3H, CH₂C₆H₅), 7.28 (t, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.22 (t, 4H, ³J_HH = 7 Hz, C₁₂H₈NS), 7.00 (t, 2H, ³J_HH = 7 Hz, C₁₂H₈NS), 6.93 (s, 2H, 2,4,6-(CH₃)₃C₆H₂), 5.85 (s, 2H, CH₂C₆H₅), 5.45 (s, 2H, NCH₂), 4.01 (s, 3H, NCH₃), 2.55 (s, 6H, 2,4,6-(CH₃)₃C₆H₂), 2.32 (s, 3H, 2,4,6-(CH₃)₃C₆H₂). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 147.2 (Pd-C), 143.7 (C₁₂H₈NS and 2,4,6-(CH₃)₃C₆H₂), 140.2 (C₂N₃), 139.8 (2,4,6-(CH₃)₃C₆H₂), 138.7 (NC), 136.2 (2,4,6-(CH₃)₃C₆H₂), 133.6 (CH₂C₆H₅), 129.8 (CH₂C₆H₅), 128.8 (CH₂C₆H₅), 128.7 (CH₂C₆H₅), 128.4 (C₁₂H₈NS), 127.6 (C₁₂H₈NS), 125.3 (C₁₂H₈NS), 123.6 (C₁₂H₈NS), 117.3 (C₁₂H₈NS), 59.6 (NCH₂), 45.0 (CH₂C₆H₅), 37.8 (NCH₃), 21.3 (2,4,6-(CH₃)₃C₆H₂), 19.0 (2,4,6-(CH₃)₃C₆H₂). IR data (cm^–1) KBr pellet: 3854(w), 3747 (w), 3444 (m), 3058 (w), 3031 (w), 2950 (w), 2919 (w), 2359 (w), 2188 (s), 1604 (w), 1571 (w), 1455 (s), 1371 (m), 1326 (m), 1284 (w), 1256 (w), 1224 (m), 1140 (w), 1104 (w), 1082 (w), 1038 (w), 933 (w), 889 (w), 837 (w), 757 (s), 708 (w), 645 (w), 597 (w), 524 (w). HRMS (ESI): calcd for [C₃₃H₃₁N₅I₂PdS–I]⁺, 762.0374; found, 762.0383. Anal. Calcd for C₃₃H₃₁N₅I₂PdS: C, 44.54; H, 3.51; N, 7.87; S, 3.60. Found: C, 45.27; H, 3.57; N, 7.49; S, 2.86%.

Synthesis of trans-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]₂PdI₂ (6)

1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazolium iodide (3) (0.256 g, 0.500 mmol) and Pd(OAc)₂ (0.056 g, 0.250 mmol) were dissolved in ca. 15 mL of 1,4-dioxane and then refluxed for 24 h. The resulting reaction mixture was filtered through Celite and further purified by column chromatography with silica gel as the stationary phase and by elution with petroleum ether/ethyl acetate (80:20 v/v) mixture to get the product as a yellow solid (6) (0.261 g, 93%). Both the ¹H NMR and ¹³C{¹H} NMR spectra showed the presence of two isomers, trans-anti and trans-syn, in ca. 1.7:1 ratio, respectively. ¹H NMR (CDCl₃, 400 MHz, 25 °C) (major): δ 7.46 (d, 4H, ³J_HH = 7 Hz, C₁₂H₈NS), 7.35–7.31 (m, 2H, CH₂C₆H₅), 7.21–7.13 (m, 5H, C₁₂H₈NS and CH₂C₆H₅), 7.01 (t, 2H, ³J_HH = 8 Hz, C₁₂H₈NS), 6.04 (s, 2H, CH₂C₆H₅), 5.27 (s, 2H, NCH₂), 4.03 (s, 2H, NCH₃). (Minor) δ 7.39 (d, 4H, ³J_HH = 7 Hz, C₁₂H₈NS), 7.31–7.29 (m, 2H, CH₂C₆H₅), 7.26–7.21 (m, 5H, C₁₂H₈NS and CH₂C₆H₅), 6.97 (t, 2H, ³J_HH = 8 Hz, C₁₂H₈NS), 5.85 (s, 2H, CH₂C₆H₅), 5.64 (s, 2H, NCH₂), 4.01 (s, 2H, NCH₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): (major) δ 156.4 (Pd-C), 143.7 (C₁₂H₈NS), 140.5 (C₂N₃), 134.4 (CH₂C₆H₅), 128.9 (CH₂C₆H₅), 128.7 (2 CH₂C₆H₅), 128.3 (C₁₂H₈NS), 127.5 (C₁₂H₈NS), 125.0 (C₁₂H₈NS), 123.4 (C₁₂H₈NS), 117.5 (C₁₂H₈NS), 58.7 (NCH₂), 45.3 (CH₂C₆H₅), 37.4 (NCH₃). (Minor) δ 156.7 (Pd-C), 143.9 (C₁₂H₈NS), 140.1 (C₂N₃), 134.5 (CH₂C₆H₅), 129.1 (CH₂C₆H₅), 128.6 (2 CH₂C₆H₅), 128.3 (C₁₂H₈NS), 127.7 (C₁₂H₈NS), 125.1 (C₁₂H₈NS), 123.4 (C₁₂H₈NS), 117.2 (C₁₂H₈NS), 59.0 (NCH₂), 45.5 (CH₂C₆H₅), 37.5 (NCH₃). IR data (cm^–1) KBr pellet: 3451(m), 3058 (m), 2927 (m), 2851 (w), 2728 (w), 2581 (w), 1943 (w), 1738 (w), 1591 (m), 1571 (m), 1484 (m), 1453 (s), 1369 (m), 1330 (m), 1286 (m), 1257 (w), 1224 (m), 1153 (w), 1105 (w), 1072 (w), 1038 (w), 930 (w), 844 (w), 753 (s), 733 (s), 614 (w), 526 (w), 500 (w). HRMS (ESI): calcd for [C₄₆H₄₀I₂N₈PdS₂–I]⁺, 1001.0891; found, 1001.0906. Anal. Calcd for C₄₆H₄₀I₂N₈PdS₂: C, 48.93; H, 3.57; N, 9.92; S, 5.68. Found: C, 48.84; H, 3.20; N, 9.62; S, 5.18%.

Synthesis of cis-[1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]Pd(PPh₃)I₂ (7)

A mixture of [1-CH₂Ph-3-Me-4-(CH₂N(C₆H₄)₂S)-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) (4) (0.300 g, 0.367 mmol) and PPh₃ (0.114 g, 0.437 mmol) was dissolved in dry CH₂Cl₂ (ca. 15 mL) and stirred at room temperature for 16 h. The solvent was evaporated and the crude product thus obtained was further purified by column chromatography using silica gel as stationary phase and by elution with petroleum ether/ethyl acetate (90:10 v/v) mixture to get a yellow solid (7) (0.293 g, 80%). Both the ¹H NMR and ¹³C{¹H} NMR spectra showed the presence of two isomers, cis and trans in ca.3.7:1 ratio. ¹H NMR (DMSO-d₆, 400 MHz, 25 °C) (major): δ 7.63–7.48 (m, 15H, P(C₆H₅)₃), 7.33 (d, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.28–7.19 (m, 7H, C₁₂H₈NS and CH₂C₆H₅), 7.04 (t, 4H, ³J_HH = 7 Hz, C₁₂H₈NS), 5.94 (d, 1H, ²J_HH = 14 Hz, CH₂C₆H₅), 5.40 (d, 1H, ²J_HH = 15 Hz, NCH₂), 5.07 (d, 1H, ²J_HH = 14 Hz, CH₂C₆H₅), 4.19 (d, 1H, ²J_HH = 15 Hz, NCH₂), 3.71 (s, 3H, NCH₃). (minor): δ 7.63–7.48 (m, 15H, P(C₆H₅)₃), 7.35 (d, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.28–7.19 (m, 7H, C₁₂H₈NS and CH₂C₆H₅), 7.04 (t, 4H, ³J_HH = 7 Hz, C₁₂H₈NS), 5.86 (s, 2H, CH₂C₆H₅), 5.43 (s, 2H, NCH₂), 4.05 (d, 3H, ⁴J_HH = 6 Hz, NCH₃). ¹³C{¹H} NMR (DMSO-d₆, 100 MHz, 25 °C) (major): δ 155.1 (Pd-C), 144.2 (C₂N₃), 143.7 (C₁₂H₈NS), 137.5 (P(C₆H₅)₃), 134.8 (P(C₆H₅)₃), 133.4 (P(C₆H₅)₃), 131.5 (P(C₆H₅)₃), 131.1 (CH₂C₆H₅), 130.1 (CH₂C₆H₅), 129.2 (CH₂C₆H₅), 128.9 (CH₂C₆H₅), 128.4 (C₁₂H₈NS), 127.9 (C₁₂H₈NS), 124.8 (C₁₂H₈NS), 124.1 (C₁₂H₈NS), 117.9 (C₁₂H₈NS), 58.6 (NCH₂), 43.1 (CH₂C₆H₅), 38.5 (NCH₃). (Minor): δ 155.1 (Pd-C), 144.1 (C₂N₃), 143.6 (C₁₂H₈NS), 137.5 (P(C₆H₅)₃), 135.2 (P(C₆H₅)₃), 132.5 (P(C₆H₅)₃), 132.0 (P(C₆H₅)₃), 130.6 (CH₂C₆H₅), 129.6 (CH₂C₆H₅), 129.1 (CH₂C₆H₅), 128.8 (CH₂C₆H₅), 128.3 (C₁₂H₈NS), 127.9 (C₁₂H₈NS), 124.9 (C₁₂H₈NS), 123.8 (C₁₂H₈NS), 117.6 (C₁₂H₈NS), 59.1 (NCH₂), 44.6 (CH₂C₆H₅), 38.0 (NCH₃). ³¹P{¹H} NMR (CDCl₃, 162 MHz, 25 °C) (Major): δ 25.0 (Pd–P). (Minor): δ 15.9 (Pd–P) IR data (cm^–1) KBr pellet: 3450(s), 3052 (w), 2967 (w), 2925 (w), 1633 (m), 1480 (w), 1456 (s), 1435 (s), 1370 (w), 1314 (m), 1257 (m), 1223 (w), 1159 (w), 1093 (w), 1072 (w), 999 (w), 952 (w), 899 (w), 836 (w), 815 (w), 753 (s), 697 (s), 663 (w), 618 (w), 527 (m), 512 (m). HRMS (ESI): calcd for [C₄₁H₃₅I₂N₄PPdS–I]⁺, 879.0394; found, 879.0409. Anal. Calcd for C₄₁H₃₅I₂N₄PPdS: C, 48.90; H, 3.50; N, 5.56; S, 3.18. Found: C, 49.05; H, 3.66; N, 5.72; S; 3.30%.

General Procedure for the Synthesis of Carbodimides Using Azide–Isocyanide Cross-Coupling as Catalyzed by Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4–7) Complexes (Table 1, Entries 1–10)

In a typical catalysis run, a 20 mL reaction vial was charged with a mixture of palladium complex 4/5/6/7 (0.003 mmol, 1 mol %) and K₂CO₃ (1.10 mmol), and then PhN₃ (0.369 mmol) and PhCH₂NC (0.443 mmol) were added to it, followed by 5 mL of toluene, and the reaction mixture was heated at 50 °C for 12 h. Then it was cooled to room temperature, filtered, and subsequently purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data.

General Procedure for the Blank Experiment

In a typical blank catalysis run, a mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product thus obtained was analyzed by ¹H NMR spectroscopy and GC–MS (entry 1, Supporting Information, Table S12).

General Procedure for the Control Experiment

The following different control runs were performed.

• (i)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and K₂CO₃ (1.10 mmol) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The crude product thus obtained was analyzed by ¹H and ¹³C{¹H} NMR spectroscopy, and GC–MS (entry 2, Supporting Information, Table S12).
• (ii)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), ligand 3 (0.003 mmol, 1 mol %), and K₂CO₃ (1.10 mmol) was heated for 12 h at 50 °C. The crude product thus obtained was analyzed by ¹H and ¹³C{¹H} NMR spectroscopy, and GC–MS (entry 3, Supporting Information, Table S12).
• (iii)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and [Pd₂(dba)₃] (1 mol %) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data (entry 4, Supporting Information, Table S12).
• (iv)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), [Pd₂(dba)₃] (1 mol %), and K₂CO₃ (1.10 mmol) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data (entry 5, Supporting Information, Table S12).
• (v)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), [(CH₃CN)₂PdCl₂] (1 mol %), and K₂CO₃ (1.10 mmol) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data (entry 6, Supporting Information, Table S12).
• (vi)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), [trans-[1,3-(2,6-(i-Pr)₂C₆H₃)₂-imidazol-2-ylidene]PdCl₂(NC₅H₅)] (1 mol %), and K₂CO₃ (1.10 mmol) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data (entry 7, Supporting Information, Table S12).
• (vii)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), trans-[1-Ph-3-Me-4-CH₂Ph-1,2,3-triazol-5-ylidene]PdI₂(NC₅H₅) (0.003 mmol, 1 mol %), and K₂CO₃ (1.10 mmol) in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data (entry 8, Supporting Information, Table S12).
• (viii)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and complex 4 (0.003 mmol, 1 mol %) was heated for 12 h at 50 °C. The crude product thus obtained was analyzed by ¹H and ¹³C{¹H} NMR spectroscopy and GC–MS (entry 9, Supporting Information, Table S12).
• (ix)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), complex 4 (0.003 mmol, 1 mol %), and K₂CO₃ (1.10 mmol) was heated for 12 h at 50 °C. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS and elemental analysis data (entry 10, Supporting Information, Table S12).

General Procedure for the Hg Drop Test

• (i).In a typical Hg drop catalysis run, a mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and catalyst 4 (0.003 mmol, 1 mol %), K₂CO₃ (1.10 mmol) and excess Hg⁰ in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS and elemental analysis data (entry 11, Supporting Information, Table S12).
• (ii).In a typical Hg drop catalysis run, a mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and catalyst 5 (0.003 mmol, 1 mol %), with K₂CO₃ (1.10 mmol) and excess Hg⁰ in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS and elemental analysis data (entry 12, Supporting Information, Table S12).
• (iii).In a typical Hg drop catalysis run, a mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and catalyst 6 (0.003 mmol, 1 mol %), with K₂CO₃ (1.10 mmol) and excess Hg⁰ in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS and elemental analysis data (entry 13, Supporting Information, Table S12).
• (iv).In a typical Hg drop catalysis run, a mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), and catalyst 7 (0.003 mmol, 1 mol %), with K₂CO₃ (1.10 mmol) and excess Hg⁰ in toluene (ca. 5 mL) was heated for 12 h at 50 °C. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product thus obtained was purified by column chromatography using silica gel (neutralized by triethylamine) as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS and elemental analysis data (entry 14, Supporting Information, Table S12).

General Procedure for the Mass Experiment

In a typical mass experiment run, a mixture of catalyst 4–7 (0.01 mmol, 1 mol %) and K₂CO₃ (3 mmol) in 5.0 mL of toluene was heated at 50 °C for 30 min, and then an aliquot from the reaction mixture was analyzed by ESI-MS, where the Pd(0) species 4a (Figure 6 and Supporting Information, Figure S222), 6a (Supporting Information, Figures S234 and S235), and 7a (Supporting Information, Figures S230 and S231) were detected.

In a typical mass experiment run, a mixture of PhN₃ (1 mmol), catalyst 4–7 (0.01 mmol, 1 mol %), and K₂CO₃ (3 mmol) in 5.0 mL of toluene was heated at 50 °C for 30 min, and then an aliquot from the reaction mixture was analyzed by ESI-MS, where the Pd bound nitrene species 4b (Figure 7 and Supporting Information, Figure S223) and 5b (Supporting Information, Figures S226 and S227) were detected.

In a typical mass experiment run, a mixture of PhN₃ (1 mmol), PhCH₂NC (1.2 mmol), catalyst 4–7 (0.01 mmol, 1 mol %), and K₂CO₃ (3 mmol) in 5.0 mL of toluene was heated at 50 °C for 1.5 h, and then an aliquot from the reaction mixture was analyzed by ESI-MS, where the species C (Figure 8 and Supporting Information, Figures S224, S225, S228, S229, S232, and S233) and 6c (Supporting Information, Figure S236 and S237) were detected.

General Procedure for the XPS Experiment

The following different XPS runs were performed.

• (i)Complex 4 (0.030 mmol) was heated for 24 h in 5 mL of toluene at 100 °C, and then the solvent was evaporated and dried. The crude product thus obtained was analyzed by XPS (Supporting Information, Figure S239).
• (ii)Complex 5 (0.030 mmol) was heated for 24 h in 5 mL of toluene at 100 °C, and then the solvent was evaporated and dried. The crude product thus obtained was analyzed by XPS (Supporting Information, Figure S241).
• (iii)Complex 6 (0.030 mmol) was heated for 24 h in 5 mL of toluene at 100 °C, and then the solvent was evaporated and dried. The crude product thus obtained was analyzed by XPS (Supporting Information, Figure S243).
• (iv)Complex 7 (0.030 mmol) was heated for 24 h in 5 mL of toluene at 100 °C, and then the solvent was evaporated and dried. The crude product thus obtained was analyzed by XPS (Supporting Information, Figure S245).
• (v)A mixture of PhN₃ (0.369 mmol), PhCH₂NC (0.443 mmol), complex 4 (0.030 mmol, 10 mol %), and K₂CO₃ (1.10 mmol) was heated for 12 h in 5 mL of toluene at 50 °C, and then the solvent was evaporated and dried. The crude product thus obtained was analyzed by XPS (Supporting Information, Figure S246).

Synthesis of N-((Benzylimino)methylene)aniline (8)⁶⁸

Yields: 0.068 g, 88% (4), 0.060 g, 79% (5), 0.051 g, 66% (6), 0.036 g, 48% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.42–7.40 (m, 4H, CH₂C₆H₅), 7.36–7.33 (m, 1H, CH₂C₆H₅), 7.28 (t, 2H, ³J_HH = 7 Hz, C₆H₅), 7.13 (t, 1H, ³J_HH = 7 Hz, C₆H₅), 7.03 (d, 2H, ³J_HH = 7 Hz, C₆H₅), 4.60 (s, 2H, CH₂C₆H₅). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 140.0 (C₆H₅), 137.8 (CH₂C₆H₅), 137.3 (NCN), 129.3 (C₆H₅), 128.8 (C₆H₅), 127.8 (C₆H₅), 127.4 (CH₂C₆H₅), 124.9 (CH₂C₆H₅), 123.6 (CH₂C₆H₅), 50.5 (CH₂C₆H₅). GC–MS (ESI): m/z = 208 [M]⁺. Anal. Calcd for C₁₄H₁₂N₂: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.08; H, 5.74; N, 13.05%.

Synthesis of N-((Tolylimino)methylene)aniline (9)⁶⁹

Yields: 0.072 g, 94% (4), 0.065 g, 85% (5), 0.055 g, 74% (6), 0.040 g, 52% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.33 (t, 2H, ³J_HH = 7 Hz, C₆H₅), 7.19 (d, 3H, ³J_HH = 7 Hz, C₆H₅), 7.14 (d, 2H, ³J_HH = 8 Hz, C₆H₄CH₃), 7.09 (d, 2H, ³J_HH = 8 Hz, C₆H₄CH₃), 2.34 (s, 3H, C₆H₄CH₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 138.7 (C₆H₅), 135.6 (NCN), 135.5 (C₆H₄CH₃), 130.1 (C₆H₅), 129.5 (C₆H₅), 125.5 (C₆H₅), 124.2 (C₆H₄CH₃), 124.1 (C₆H₄CH₃), 123.9 (C₆H₄CH₃), 21.0 (C₆H₄CH₃). GC–MS (ESI): m/z = 208 [M]⁺. Anal. Calcd for C₁₄H₁₂N₂: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.19; H, 5.96; N, 13.54%.

Synthesis of N-((Xylylimino)methylene)aniline (10)¹⁴

Yields: 0.064 g, 78% (4), 0.051 g, 62% (5), 0.041 g, 50% (6), 0.019 g, 24% (7).

¹H NMR (CDCl₃, 500 MHz, 25 °C): δ 7.33 (t, 2H, ³J_HH = 7 Hz, C₆H₅), 7.18 (d, 2H, ³J_HH = 7 Hz, C₆H₅), 7.14 (t, 1H, ³J_HH = 7 Hz, 2,6-(CH₃)₂C₆H₃), 7.05 (d, 2H, ³J_HH = 7 Hz, 2,6-(CH₃)₂C₆H₃), 7.00 (t, 1H, ³J_HH = 7 Hz, C₆H₅), 2.40 (s, 6H, 2,6-(CH₃)₂C₆H₃). ¹³C{¹H} NMR (CDCl₃, 125 MHz, 25 °C): δ 139.8 (C₆H₅), 134.9 (2,6-(CH₃)₂C₆H₃), 132.8 (2,6-(CH₃)₂C₆H₃), 131.5 (NCN), 129.5 (C₆H₅), 128.2 (C₆H₅), 125.1 (C₆H₅), 124.7 (2,6-(CH₃)₂C₆H₃), 123.7 (2,6-(CH₃)₂C₆H₃), 19.0 (2,6-(CH₃)₂C₆H₃). GC–MS (ESI): m/z = 222 [M]⁺. Anal. Calcd for C₁₅H₁₂N₂: C, 81.05; H, 6.35; N, 12.60. Found: C, 81.71; H, 6.60; N, 12.37%.

Synthesis of N-((Mesityimino)methylene)aniline (11)⁷⁰

Yields: 0.053 g, 61% (4), 0.046 g, 53% (5), 0.034 g, 39% (6), 0.014 g, 16% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.32 (t, 2H, ³J_HH = 7 Hz, C₆H₅), 7.18–7.11 (m, 3H, C₆H₅), 6.87 (s, 2H, 2,4,6-(CH₃)₃C₆H₂), 2.36 (s, 6H, 2,4,6-(CH₃)₃C₆H₂), 2.27 (s, 3H, 2,4,6-(CH₃)₃C₆H₂). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 140.2 (C₆H₅), 134.9 (2,4,6-(CH₃)₃C₆H₂), 132.7 (2,4,6-(CH₃)₃C₆H₂), 132.1 (2,4,6-(CH₃)₃C₆H₂), 131.8 (NCN), 129.4 (C₆H₅), 128.9 (C₆H₅), 124.6 (C₆H₅), 123.6 (2,4,6-(CH₃)₃C₆H₂), 20.8 (2,4,6-(CH₃)₃C₆H₂), 18.9 (2,4,6-(CH₃)₃C₆H₂). GC–MS (ESI): m/z = 236 [M]⁺. Anal. Calcd for C₁₆H₁₆N₂: C, 81.32; H, 6.82; N, 11.85. Found: C, 81.31; H, 6.74; N, 11.68%.

Synthesis of N-((Cyclohexyimino)methylene)aniline (12)⁷¹

Yields: 0.069 g, 94% (4), 0.068 g, 92% (5), 0. 056 g, 76% (6), 0.023 g, 32% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.31 (t, 2H, ³J_HH = 7 Hz, C₆H₅), 7.13–7.10 (m, 3H, C₆H₅), 3.53–3.46 (m, 1H, C₆H₁₁), 2.06–2.01 (m, 2H, C₆H₁₁), 1.83–1.77 (m, 2H, C₆H₁₁), 1.66–1.47 (m, 3H, C₆H₁₁), 1.42–1.28 (m, 3H, C₆H₁₁). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 140.9 (C₆H₅), 136.2 (NCN), 129.3 (C₆H₅), 124.5 (C₆H₅), 123.3 (C₆H₅), 56.6 (C₆H₁₁), 34.9 (C₆H₁₁), 25.3 (C₆H₁₁), 24.3 (C₆H₁₁). GC–MS (ESI): m/z = 200 [M]⁺. Anal. Calcd for C₁₃H₁₆N₂: C, 77.96; H, 8.05; N, 13.99. Found: C, 78.73; H, 8.28; N, 13.20%.

Synthesis of N-((Cyclohexylimino)methylene)cyclohexylamine (13)⁷¹

Yields: 0.064 g, 84% (4), 0.051 g, 67% (5), 0.041 g, 54% (6), 0.028 g, 37% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 3.20–3.14 (m, 1H, C₆H₁₁), 1.91–1.89 (m, 2H, C₆H₁₁), 1.73–1.70 (m, 2H, C₆H₁₁), 1.57–1.53 (m, 1H, C₆H₁₁), 1.35–1.16 (m, 5H, C₆H₁₁). ¹³C{¹H} NMR (CDCl₃, 125 MHz, 25 °C): δ 139.8 (NCN), 55.7 (C₆H₁₁), 34.9 (C₆H₁₁), 25.4 (C₆H₁₁), 24.7 (C₆H₁₁). GC–MS (ESI): m/z = 206 [M]⁺. Anal. Calcd for C₁₃H₂₂N₂: C, 75.68; H, 10.75; N, 13.58. Found: C, 76.19; H, 10.75; N, 13.56%.

Synthesis of N-((Tolylimino)methylene)cyclohexylamine (14)⁷²

Yields: 0.054 g, 66% (4), 0.043 g, 52% (5), 0. 032 g, 39% (6), 0.023 g, 28% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.37–7.36 (m, 4H, CH₂C₆H₅), 7.32–7.29 (m, 1H, CH₂C₆H₅), 7.04 (d, 2H, ³J_HH = 8 Hz, C₆H₄CH₃), 6.88 (d, 2H, ³J_HH = 8 Hz, C₆H₄CH₃), 4.55 (s, 2H, CH₂C₆H₅), 2.29 (s, 3H, C₆H₄CH₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 137.9 (C₆H₄CH₃), 137.8 ((NCN), 137.0 CH₂C₆H₅), 134.6 (C₆H₄CH₃), 129.9 (C₆H₄CH₃), 128.7 (C₆H₄CH₃), 127.7 (CH₂C₆H₅), 127.4 (CH₂C₆H₅), 123.4 (CH₂C₆H₅), 50.5 (CH₂C₆H₅), 20.9 (C₆H₄CH₃). GC–MS (ESI): m/z = 222 [M]⁺. Anal. Calcd for C₁₅H₁₄N₂: C, 81.05; H, 6.35; N, 12.60. Found: C, 79.80; H, 6.32; N, 12.20%.

Synthesis of N-((Tolylimino)methylene)cyclohexylamine (15)

Yields: 0.049 g, 56% (4), 0.033 g, 38% (5), 0. 023 g, 26% (6), 0.010 g, 12% (7).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.41–7.34 (m, 4H, CH₂C₆H₅), 7.31–7.28 (m, 1H, CH₂C₆H₅), 7.06 (td, 1H, ³J_HH = 8 Hz, ⁴J_HH = 2 Hz, C₆H₄OCH₃), 6.99 (d, 2H, ³J_HH = 8 Hz, C₆H₄OCH₃), 6.85 (t, 1H, ³J_HH = 8 Hz, C₆H₄OCH₃), 6.84 (d, 2H, ³J_HH = 8 Hz, C₆H₄OCH₃), 4.58 (s, 2H, CH₂C₆H₅), 3.76 (s, 3H, C₆H₄OCH₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 154.0 (C₆H₄OCH₃), 138.1 (CH₂C₆H₅), 128.6 (C₆H₄OCH₃), 128.4 (NCN), 127.5 (CH₂C₆H₅), 127.4 (2 C₆H₄OCH₃), 125.6 (CH₂C₆H₅), 124.7 (CH₂C₆H₅), 120.9 (C₆H₄OCH₃), 111.0 (C₆H₄OCH₃), 55.8 (C₆H₄OCH₃), 50.6 (CH₂C₆H₅). GC–MS (ESI): m/z = 238 [M]⁺. Anal. Calcd for C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.26; H, 5.84; N, 11.45%.

Synthesis of N-((4-Fluorophenylimino)methylene)cyclohexylamine (16)

Yields: 0.082 g, 99% (4), 0.077 g, 93% (5), 0. 067 g, 80% (6), 0.050 g, 61% (7).

¹H NMR (C₆D₆, 400 MHz, 25 °C): δ 7.05–7.04 (m, 3H, CH₂C₆H₅), 7.03–6.94 (m, 2H, CH₂C₆H₅), 6.75–6.71 (m, 2H, C₆H₄F), 6.60–6.56 (m, 2H, C₆H₄F), 4.00 (s, 2H, CH₂C₆H₅). ¹³C{¹H} NMR (C₆D₆, 100 MHz, 25 °C): δ 161.1 (d, ¹J_CF = 244 Hz, C₆H₄F), 137.9 (CH₂C₆H₅), 137.1 (NCN), 132.0 (CH₂C₆H₅), 131.4 (d, ⁴J_CF = 4 Hz, C₆H₄F), 128.5 (CH₂C₆H₅), 127.2 (CH₂C₆H₅), 124.8 (d, ³J_CF = 8 Hz, C₆H₄F), 115.9 (d, ²J_CF = 23 Hz, C₆H₄F), 49.9 (CH₂C₆H₅). ¹⁹F{¹H} NMR (C₆D₆, 376 MHz, 25 °C): δ – 117.71 (C₆H₄F). GC–MS (ESI): m/z = 226 [M]⁺. Anal. Calcd for C₁₄H₁₁N₂F: C, 74.32; H, 4.90; N, 12.38. Found: C, 75.31; H, 5.12; N, 11.74%.

Synthesis of N-((3,5-Bis(trifluoromethyl)phenylimino)methylene)cyclohexylamine (17)

Yields: 0.115 g, 91% (4), 0.095 g, 75% (5), 0. 082 g, 65% (6), 0.050 g, 44% (7).

¹H NMR (C₆D₆, 400 MHz, 25 °C): δ 7.37 (s, 1H, C₆H₃(CF₃)₂), 7.08 (s, 2H, C₆H₃(CF₃)₂), 7.06–7.01 (m, 3H, CH₂C₆H₅), 6.95 (d, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 3.86 (s, 2H, CH₂C₆H₅). ¹³C{¹H} NMR (C₆D₆, 100 MHz, 25 °C): δ 143.1 (C₆H₃(CF₃)₂), 137.3 (CH₂C₆H₅), 134.6 (NCN), 132.4 (q, ²J_CF = 33 Hz, C₆H₃(CF₃)₂), 131.7 (CH₂C₆H₅), 128.8 (CH₂C₆H₅), 127.1 (CH₂C₆H₅), 123.4 (d, ⁴J_CF = 3 Hz, C₆H₃(CF₃)₂), 123.1 (q, ¹J_CF = 273 Hz, C₆H₃(CF₃)₂), 117.5 (quin, ³J_CF = 4 Hz, C₆H₃(CF₃)₂), 49.7 (CH₂C₆H₅). ¹⁹F{¹H} NMR (C₆D₆, 376 MHz, 25 °C): δ – 62.86 (C₆H₃(CF₃)₂). GC–MS (ESI): m/z = 344 [M]⁺. Anal. Calcd for C₁₆H₁₀N₂F₆: C, 55.82; H, 2.93; N, 8.14. Found: C, 55.54; H, 3.79; N, 8.98%.

General Procedure for the Synthesis of Benzoxazole Derivatives Using Azide and Isocyanide Cross-Coupling as Catalyzed by a Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4) Complex (Table 3, Entries 1–5)

In a typical catalysis run, a 20 mL reaction vial was charged with a mixture of palladium complex 4 (0.01 mmol, 1 mol %) and K₂CO₃ (3.00 mmol), and then the corresponding azide (1.00 mmol) and isocyanide (1.20 mmol) were added to it, followed by 5 mL of toluene, and the reaction mixture was heated at 50 °C for 12 h. The reaction mixture was cooled to room temperature, filtered, and subsequently purified by column chromatography using silica gel as a stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data.

Synthesis of N-Cyclohexylbenzooxazol-2-amine (18)⁷³

Yield: 0.181 g, 84% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.35 (d, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.22 (d, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.14 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.00 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 5.08 (br, 1H, NH), 3.80–3.71 (m, 1H, C₆H₁₁), 2.14–2.11 (m, 2H, C₆H₁₁), 1.79–1.74 (m, 2H, C₆H₁₁), 1.67–1.62 (m, 1H, C₆H₁₁), 1.48–1.38 (m, 2H, C₆H₁₁), 1.34–1.25 (m, 3H, C₆H₁₁). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 161.4 (OCN of C₇H₄NO), 148.3 (C₆H₄ of C₇H₄NO), 143.1 (C₆H₄ of C₇H₄NO), 123.8 (C₆H₄ of C₇H₄NO), 120.6 (C₆H₄ of C₇H₄NO), 116.2 (C₆H₄ of C₇H₄NO), 108.6 (C₆H₄ of C₇H₄NO), 52.0 (C₆H₁₁), 33.4 (C₆H₁₁), 25.4 (C₆H₁₁), 24.7 (C₆H₁₁). GC–MS (ESI): m/z = 216 [M]⁺. Anal. Calcd for C₁₃H₁₆N₂O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.34; H, 7.08; N, 12.87%.

Synthesis of N-(2,6-dimethylphenyl)lbenzooxazol-2-amine (19)⁷⁴

Yield: 0.128 g, 54% (4).

¹H NMR (DMSO-d₆, 400 MHz, 25 °C): δ 9.58 (br, 1H, NH), 7.39 (d, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.22 (d, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.17–7.10 (m, 4H, C₇H₄NO and 2,6-(CH₃)₂C₆H₃), 7.01 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 2.20 (s, 6H, 2,6-(CH₃)₂C₆H₃). ¹³C{¹H} NMR (DMSO-d₆, 100 MHz, 25 °C): δ 160.3 (OCN of C₇H₄NO), 148.0 (C₆H₄ of C₇H₄NO), 142.8 (C₆H₄ of C₇H₄NO), 135.6 (2,6-(CH₃)₂C₆H₃), 134.9 (2,6-(CH₃)₂C₆H₃), 128.2 (2,6-(CH₃)₂C₆H₃), 126.9 (2,6-(CH₃)₂C₆H₃), 123.8 (C₆H₄ of C₇H₄NO), 120.6 (C₆H₄ of C₇H₄NO), 115.7 (C₆H₄ of C₇H₄NO), 108.8 (C₆H₄ of C₇H₄NO), 17.9 (2,6-(CH₃)₂C₆H₃). GC–MS (ESI): m/z = 238 [M]⁺. Anal. Calcd for C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.28; H, 6.59; N, 11.43%

Synthesis of N-tert-Butylbenzooxazol-2-amine (20)⁷⁴

Yield: 0.169 g, 89% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.39 (d, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.27 (d, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.18 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.04 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 5.46 (br, 1H, NH), 1.52 (s, 9H, C(CH₃)₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 160.8 (OCN of C₇H₄NO), 148.0 (C₆H₄ of C₇H₄NO), 142.5 (C₆H₄ of C₇H₄NO), 123.8 (C₆H₄ of C₇H₄NO), 120.7 (C₆H₄ of C₇H₄NO), 116.2 (C₆H₄ of C₇H₄NO), 108.6 (C₆H₄ of C₇H₄NO), 52.1 (C(CH₃)₃), 29.2 (C(CH₃)₃). GC–MS (ESI): m/z = 190 [M]⁺. Anal. Calcd for C₁₁H₁₄N₂O: C, 69.45; H, 7.42; N, 14.73. Found: C, 68.76; H, 6.54; N, 14.37%.

Synthesis of N-Mesiylbenzooxazol-2-amine (21)

Yield: 0.083 g, 33% (4).

¹H NMR (DMSO-d₆, 400 MHz, 25 °C): δ 9.03 (br, 1H, NH), 6.91 (s, 2H, 2,4,6-(CH₃)₃C₆H₂), 6.71 (dd, 1H, ³J_HH = 8 Hz, C₇H₄NO), 6.64 (dd, 1H, ³J_HH = 8 Hz, C₇H₄NO), 6.57 (td, 1H, ³J_HH = 8 Hz, C₇H₄NO), 6.43 (td, 1H, ³J_HH = 8 Hz, C₇H₄NO), 2.26 (s, 6H, 2,4,6-(CH₃)₃C₆H₂), 2.22 (s, 3H, 2,6-(CH₃)₃C₆H₂). ¹³C{¹H} NMR (DMSO-d₆, 100 MHz, 25 °C): δ 167.8 (OCN of C₇H₄NO), 144.5 (C₆H₄ of C₇H₄NO), 139.2 (C₆H₄ of C₇H₄NO), 136.9 (2,4,6-(CH₃)₃C₆H₂), 134.4 (2,4,6-(CH₃)₃C₆H₂), 128.8 2,4,6-(CH₃)₃C₆H₂), 123.7 (2,4,6-(CH₃)₃C₆H₂), 120.0 (C₆H₄ of C₇H₄NO), 117.0 (C₆H₄ of C₇H₄NO), 115.0 (C₆H₄ of C₇H₄NO), 114.8 (C₆H₄ of C₇H₄NO), 21.1 (2,4,6-(CH₃)₃C₆H₂), 18.6 (2,4,6-(CH₃)₃C₆H₂). GC–MS (ESI): m/z = 252 [M]⁺. Anal. Calcd for C₁₆H₁₆N₂O: C, 76.16; H, 6.39; N, 11.10. Found: C, 76.47; H, 6.59; N, 10.20%.

Synthesis of N-Benzylbenzooxazol-2-amine (22)⁷⁵

Yield: 0.162 g, 72% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.41–7.24 (m, 6H, C₇H₄NO and CH₂C₆H₅), 7.16 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 7.03 (t, 1H, ³J_HH = 8 Hz, C₇H₄NO), 5.98 (br, 1H, NH), 4.67 (s, 9H, CH₂C₆H₅). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 162.1 (OCN of C₇H₄NO), 148.5 (C₆H₄ of C₇H₄NO), 142.7 (C₆H₄ of C₇H₄NO), 137.7 (CH₂C₆H₅), 128.8 (CH₂C₆H₅), 127.8 (CH₂C₆H₅), 127.6 (CH₂C₆H₅), 124.0 (C₆H₄ of C₇H₄NO), 120.9 (C₆H₄ of C₇H₄NO), 116.3 (C₆H₄ of C₇H₄NO), 108.8 (C₆H₄ of C₇H₄NO), 47.0 (CH₂C₆H₅). GC–MS (ESI): m/z = 224 [M]⁺. Anal. Calcd for C₁₄H₁₂N₂O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.30; H, 5.68; N, 13.38%.

General Procedure for the Synthesis of Benzimidazole Derivatives Using Azide and Isocyanide Cross-Coupling as Catalyzed by a Phenothiazine-Derived Mesoionic Singlet Carbene Palladium (4) Complex (Table 4, Entries 1–5)

In a typical catalysis run, a 20 mL reaction vial was charged with a mixture of palladium complex 4 (0.01 mmol, 1 mol %) and K₂CO₃ (3.00 mmol), and then the corresponding azide (1.00 mmol) and isocyanide (1.20 mmol) were added to it, followed by 5 mL of toluene, and the reaction mixture was heated at 50 °C for 12 h. The reaction mixture was cooled to room temperature, CuI (0.100 mmol, 10 mol %), 1,10-phenanthroline (0.200 mmol, 20 mol %), Cs₂CO₃ (2.00 mmol), and N-heterocycle (1.1 mmol) were added to it and heated at 80 °C for 20 h. Then it was filtered, the solvent was evaporated, and the result was subsequently purified by column chromatography using silica gel as the stationary phase and by elution with a mixed medium of petroleum ether/EtOAc to give the desired product, as characterized by ¹H and ¹³C{¹H} NMR spectroscopy, GC–MS, and elemental analysis data.

Synthesis of 4-(1-Benzyl-1H-benzimidazol-2-yl)morpholine (23)⁷⁶

Yield: 0.187 g, 64% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.65 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 7.34–7.29 (m, 3H, CH₂C₆H₅), 7.19 (td, 1H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₇H₄N₂), 7.14 (d, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.09 (td, 1H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₇H₄N₂), 7.02 (d, 1H, ³J_HH = 7 Hz, C₇H₄N₂), 5.23 (s, 2H, CH₂C₆H₅), 3.79 (t, 4H, ³J_HH = 5 Hz, NC₄H₈O), 3.24 (t, 4H, ³J_HH = 5 Hz, NC₄H₈O). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 157.6 (NCN of C₇H₄N₂), 141.3 (C₆H₄ of C₇H₄N₂), 136.0 (C₆H₄ of C₇H₄N₂), 135.3 (CH₂C₆H₅), 128.9 (CH₂C₆H₅), 127.6 (CH₂C₆H₅), 125.9 (CH₂C₆H₅), 122.0 (C₆H₄ of C₇H₄N₂), 121.5 (C₆H₄ of C₇H₄N₂), 118.1 (C₆H₄ of C₇H₄N₂), 109.3 (C₆H₄ of C₇H₄N₂), 66.4 (NC₄H₈O), 50.8 (NC₄H₈O), 47.4 (CH₂C₆H₅). GC–MS (ESI): m/z = 293 [M]⁺. Anal. Calcd for C₁₈H₁₉N₃O: C, 73.69; H, 6.53; N, 14.32. Found: C, 73.55; H, 6.02; N, 14.02%.

Synthesis of 1-Benzyl-2-(piperidin-1-yl)-1H-benzimidazole (24)⁷⁷

Yield: 0.197 g, 68% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.63 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 7.34–7.27 (m, 3H, CH₂C₆H₅), 7.18 (d, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.17 (t, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 7.06 (t, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 6.98 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 5.20 (s, 2H, CH₂C₆H₅), 3.20 (t, 4H, ³J_HH = 5 Hz, NC₅H₁₀), 1.67–1.60 (m, 6H, NC₅H₁₀). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 159.0 (NCN of C₇H₄N₂), 141.6 (C₆H₄ of C₇H₄N₂), 136.4 (C₆H₄ of C₇H₄N₂), 135.3 (CH₂C₆H₅), 128.8 (CH₂C₆H₅), 127.5 (CH₂C₆H₅), 126.1 (CH₂C₆H₅), 121.7 (C₆H₄ of C₇H₄N₂), 121.1 (C₆H₄ of C₇H₄N₂), 117.8 (C₆H₄ of C₇H₄N₂), 109.2 (C₆H₄ of C₇H₄N₂), 51.8 (NC₅H₁₀), 47.6 (CH₂C₆H₅), 25.6 (NC₅H₁₀), 24.1 (NC₅H₁₀). GC–MS (ESI): m/z = 291 [M]⁺. Anal. Calcd for C₁₉H₂₁N₃: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.78; H, 7.37; N, 14.50%.

Synthesis of 1-Benzyl-2-(pyrrolidin-1-yl)-1H-benzimidazole (25)⁷⁶

Yield: 0.083 g, 33% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.55 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 7.34–7.27 (m, 4H, C₇H₄N₂ and CH₂C₆H₅), 7.55 (d, 2H, ³J_HH = 7 Hz, CH₂C₆H₅), 7.01 (t, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 6.97 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 5.28 (s, 2H, CH₂C₆H₅), 3.58 (br, 4H, NC₄H₈), 1.91 (br, 4H, NC₄H₈). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 161.0 (NCN of C₇H₄N₂), 141.6 (C₆H₄ of C₇H₄N₂), 138.6 (C₆H₄ of C₇H₄N₂), 136.7 (CH₂C₆H₅), 128.9 (CH₂C₆H₅), 127.5 (CH₂C₆H₅), 125.7 (CH₂C₆H₅), 122.0 (C₆H₄ of C₇H₄N₂), 120.3 (C₆H₄ of C₇H₄N₂), 116.5 (C₆H₄ of C₇H₄N₂), 108.4 (C₆H₄ of C₇H₄N₂), 50.6 (NC₄H₈), 47.9 (CH₂C₆H₅), 25.6 (NC₄H₈). GC–MS (ESI): m/z = 277 [M]⁺. Anal. Calcd for C₁₈H₁₉N₃: C, 77.95; H, 6.90; N, 15.15. Found: C, 78.21; H, 6.95; N, 14.68%.

Synthesis of 1-Benzyl-N-cyclohexyl-1H-benzimidazol-2-amine (26)⁷⁸

Yield: 0.168 g, 55% (4).

¹H NMR (CDCl₃, 400 MHz, 25 °C): δ 7.81 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 7.37–7.30 (m, 4H, CH₂C₆H₅), 7.30–7.27 (m, 1H, CH₂C₆H₅), 7.25 (t, 1H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₇H₄N₂), 6.96 (d, 1H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₇H₄N₂), 6.70 (t, 1H, ³J_HH = 7 Hz, C₇H₄N₂), 4.40 (s, 2H, CH₂C₆H₅), 3.14 (br, 1H, C₆H₁₁), 1.96–1.93 (m, 3H, C₆H₁₁), 1.62–1.59 (m, 3H, C₆H₁₁), 1.28–1.27 (m, 2H, C₆H₁₁), 1.12–1.06 (m, 2H, C₆H₁₁). ¹³C{¹H} NMR (CDCl₃, 100 MHz, 25 °C): δ 150.9 (NCN of C₇H₄N₂), 139.3 (C₆H₄ of C₇H₄N₂), 138.6 (CH₂C₆H₅), 129.3 (CH₂C₆H₅), 128.9 (C₆H₄ of C₇H₄N₂), 128.8 (CH₂C₆H₅), 127.6 (CH₂C₆H₅), 127.4 (C₆H₄ of C₇H₄N₂), 124.0 (C₆H₄ of C₇H₄N₂), 123.8 (C₆H₄ of C₇H₄N₂), 50.4 (C₆H₁₁), 46.1 (CH₂C₆H₅), 33.7 (C₆H₁₁), 25.4 (C₆H₁₁), 24.6 (C₆H₁₁). GC–MS (ESI): m/z = 305 [M]⁺. Anal. Calcd for C₂₀H₂₃N₃: C, 78.65; H, 7.59; N, 13.76. Found: C, 77.72; H, 8.47; N, 13.06%.

Synthesis of 4-(1-Cyclohexyl-1H-benzimidazol-2-yl)morpholine (27)

Yield: 0.205 g, 72% (4).

¹H NMR (CDCl₃, 500 MHz, 25 °C): δ 7.80 (d, 1H, ³J_HH = 8 Hz, C₇H₄N₂), 7.26 (t, 1H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₇H₄N₂), 6.91 (d, 1H, ³J_HH = 8 Hz, ⁴J_HH = 1 Hz, C₇H₄N₂), 6.74 (t, 1H, ³J_HH = 7 Hz, C₇H₄N₂), 3.73 (t, 4H, ³J_HH = 5 Hz, NC₄H₈O), 3.34 (t, 4H, ³J_HH = 5 Hz, NC₄H₈O), 3.14 (br, 1H, C₆H₁₁), 1.90–1.88 (m, 2H, C₆H₁₁), 1.65–1.62 (m, 2H, C₆H₁₁), 1.54–1.51 (m, 1H, C₆H₁₁), 1.24–1.18 (m, 3H, C₆H₁₁), 1.07–1.05 (m, 2H, C₆H₁₁). ¹³C{¹H} NMR (CDCl₃, 125 MHz, 25 °C): δ 155.2 (NCN of C₇H₄N₂), 139.3 (C₆H₄ of C₇H₄N₂), 129.2 (C₆H₄ of C₇H₄N₂), 124.4 (C₆H₄ of C₇H₄N₂), 123.0 (C₆H₄ of C₇H₄N₂), 66.5 (NC₄H₈O), 53.7 (C₆H₁₁), 48.5 (NC₄H₈O), 34.0 (C₆H₁₁), 25.2 (C₆H₁₁), 25.0 (C₆H₁₁). GC–MS (ESI): m/z = 285 [M]⁺. Anal. Calcd for C₁₇H₂₃N₃O: C, 71.55; H, 8.12; N, 14.72;. Found: C, 72.20; H, 9.07; N, 13.74%.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c07875. CCDC-2041824 (for 4), CCDC-2060553 (for 5), CCDC- 2123529 (for 6), and CCDC-2069000 (for 7) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data center via www.ccdc.cam.ac.uk/data_request/cif

• ¹H NMR, ¹³C{¹H} NMR, IR, HRMS, and elemental analysis data of precarbene ligands (1–3), ¹H NMR, ¹³C{¹H} NMR, IR, HRMS, elemental analysis, and XPS data of palladium carbene complexes (4–7), and ¹H NMR, ¹³C{¹H} NMR, GC–MS chromatograms, and elemental analysis data of the catalysis products (8–17), the benzoxazole derivatives (18–22), and the guanidine derivatives (23–27) (PDF)

• X-ray crystallographic data of palladium carbene complexes (4–7) (CIF)

The authors declare no competing financial interest.