Benzothiazole Nickelation: An Obstacle to the Catalytic Arylation of Azoles by Cyclopentadienyl Nickel N-Heterocyclic Carbene Complexes

: NiCp † L(NHC)] (+) complexes (Cp † = Cp ( η 5 -C 5 H 5 ), Cp* ( η 5 -C 5 Me 5 ); NHC = N-heterocyclic carbene; L = Cl − or NCMe) have been tested as pre-catalysts for the direct arylation of benzothiazole in the presence of an alkoxide. Only the pentamethylcyclopentadienyl derivative, [NiCp*Cl(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenylimidazol-2-ylidene), enabled low conversion to the desired coupling product with phenyl iodide as the electrophilic coupling partner. In contrast, all cyclopentadienyl complexes proved to be inactive. 1 H NMR studies of the “catalytic” reaction mixtures demonstrate that they cleanly convert to an unreactive C(2)-benzothiazolyl derivative, whose identity has been conﬁrmed by an independent synthesis and characterization. The latter constitutes a potential energy well that quenches all further reactivity, and provides a rare example of C(2)-metallated azolyl complex.

As we were intrigued by the incapacity of the CpNi(NHC) complexes to catalyze these direct couplings, we attempted to establish the fate of the latter under the reaction conditions. To our surprise, the 1 H NMR spectra of the reaction media (after removal of the insoluble and volatiles-see Section 3) of reactions run with 3 under various conditions of solvent (THF, toluene or 1,4-dioxane), base (LiOtBu, NaOtBu, KOtBu) and temperature (from 90 to 140 • C) systematically indicated the presence of unreacted benzothiazole and p-bromotoluene or iodobenzene, as well as the full and clean conversion of 3 to a novel CpNi(IMes) complex 7 bearing a C(2)-metallated benzothiazolyl group (see Figures S1 and S2, and Scheme 2), whose identity was confirmed by an independent synthesis (vide infra). The latter was indeed characterized by typical signals for its IMes and Cp groups, but which are shifted compared to those of 3, as well as by two apparent triplets centered at 7.11 and 6.97 ppm, which integrate for one proton each relative to the Cp and IMes signals and correspond to the H(5) and H(6) protons of a benzothiazolyl unit. However, the signals of the H(4) and H(7) overlapped with those of unreacted benzothiazole and were not unambiguously observed. Complex 7 was also observed in the attempted couplings with the cationic complex 6 ( Figure S3), highlighting a general behaviour for these CpNi(NHC) species thereof.  1 Reaction conditions: benzothiazole (1 equiv.), p-bromotoluene or iodobenzene (1.5 equiv.), LiOtBu (2 equiv.), 3-6 (5 mol %) in 1,4-dioxane at 140 °C for 16 h. 2 Conversion to the desired coupling product established by GC; average value of two runs. 3 Run at 120 °C. 4 Run with 1.5 equiv. of LiOtBu.
As we were intrigued by the incapacity of the CpNi(NHC) complexes to catalyze these direct couplings, we attempted to establish the fate of the latter under the reaction conditions. To our surprise, the 1 H NMR spectra of the reaction media (after removal of the insoluble and volatiles-see Experimental Section) of reactions run with 3 under various conditions of solvent (THF, toluene or 1,4-dioxane), base (LiOtBu, NaOtBu, KOtBu) and temperature (from 90 to 140 °C) systematically indicated the presence of unreacted benzothiazole and p-bromotoluene or iodobenzene, as well as the full and clean conversion of 3 to a novel CpNi(IMes) complex 7 bearing a C(2)-metallated benzothiazolyl group (see Figures S1 and S2, and Scheme 2), whose identity was confirmed by an independent synthesis (vide infra). The latter was indeed characterized by typical signals for its IMes and Cp groups, but which are shifted compared to those of 3, as well as by two apparent triplets centered at 7.11 and 6.97 ppm, which integrate for one proton each relative to the Cp and IMes signals and correspond to the H(5) and H(6) protons of a benzothiazolyl unit. However, the signals of the H(4) and H(7) overlapped with those of unreacted benzothiazole and were not unambiguously observed. Complex 7 was also observed in the attempted couplings with the cationic complex 6 ( Figure S3), highlighting a general behaviour for these CpNi(NHC) species thereof. 1 Reaction conditions: benzothiazole (1 equiv.), p-bromotoluene or iodobenzene (1.5 equiv.), LiOtBu (2 equiv.), 3-6 (5 mol %) in 1,4-dioxane at 140 °C for 16 h. 2 Conversion to the desired coupling product established by GC; average value of two runs. 3 Run at 120 °C. 4 Run with 1.5 equiv. of LiOtBu.
As we were intrigued by the incapacity of the CpNi(NHC) complexes to catalyze these direct couplings, we attempted to establish the fate of the latter under the reaction conditions. To our surprise, the 1 H NMR spectra of the reaction media (after removal of the insoluble and volatiles-see Experimental Section) of reactions run with 3 under various conditions of solvent (THF, toluene or 1,4-dioxane), base (LiOtBu, NaOtBu, KOtBu) and temperature (from 90 to 140 °C) systematically indicated the presence of unreacted benzothiazole and p-bromotoluene or iodobenzene, as well as the full and clean conversion of 3 to a novel CpNi(IMes) complex 7 bearing a C(2)-metallated benzothiazolyl group (see Figures S1 and S2, and Scheme 2), whose identity was confirmed by an independent synthesis (vide infra). The latter was indeed characterized by typical signals for its IMes and Cp groups, but which are shifted compared to those of 3, as well as by two apparent triplets centered at 7.11 and 6.97 ppm, which integrate for one proton each relative to the Cp and IMes signals and correspond to the H(5) and H(6) protons of a benzothiazolyl unit. However, the signals of the H(4) and H(7) overlapped with those of unreacted benzothiazole and were not unambiguously observed. Complex 7 was also observed in the attempted couplings with the cationic complex 6 ( Figure S3), highlighting a general behaviour for these CpNi(NHC) species thereof. Interestingly, although C(2)-benzoxazolyl or benzothiazolyl complexes are often proposed as intermediates in C-H/C-X couplings between heteroarenes and aryl, alkenyl or alkyl electrophiles [5,10,12,14,16,17,19,20,22,23], they remain very rare. We are indeed aware of only four related PCN-Pd [39][40][41] and NNN-Ni [23] pincer species, which have been isolated with a benzothiazolyl ligand and demonstrated to be intermediates in similar couplings. Thus, although it obviously constitutes a potential energy well, complex 7 is an interesting example of azolyl trapping in such (attempted) direct coupling. Furthermore, it is to our knowledge only the second C(2)-benzothiazolyl-nickel species reported to date [23]. Interestingly, although C(2)-benzoxazolyl or benzothiazolyl complexes are often proposed as intermediates in C-H/C-X couplings between heteroarenes and aryl, alkenyl or alkyl electrophiles [5,10,12,14,16,17,19,20,22,23], they remain very rare. We are indeed aware of only four related PCN-Pd [39][40][41] and NNN-Ni [23] pincer species, which have been isolated with a benzothiazolyl ligand and demonstrated to be intermediates in similar couplings. Thus, although it obviously constitutes a potential energy well, complex 7 is an interesting example of azolyl trapping in such (attempted) direct coupling. Furthermore, it is to our knowledge only the second C(2)-benzothiazolyl-nickel species reported to date [23].

Independent Synthesis and Characterization of the Benzothiazolyl Complex 7
To confirm the identity of 7, complex 3 was treated with a small excess of benzothiazole (1.2 equiv.) in the presence of potassium bis(trimethylsilyl)amide (KHMDS) as a base in toluene at room temperature (Scheme 3). The resulting complex was isolated in 80% yield as an air-stable green-brown powder after work-up. Full characterization by 1 H and 13 C{ 1 H} NMR, HRMS spectroscopies and CHN microanalyses confirmed the expected formulation. Thus, for instance, the 1 H NMR spectrum of 7 no longer displays the H(2) proton of benzothiazole, but displays the H(5) and H(6) protons as two Catalysts 2019, 9, 76 4 of 10 apparent triplets at 7.12 and 6.98 ppm, as seen in the spectra of the catalytic attempts (vide supra), and the H(4) and H(7) protons as two doublets at 7.58 and 7.51 ppm ( Figure S4). The Cp and IMes protons are found at values that are typical for NiCp(IMes) compounds [27][28][29][30][31][32][33][35][36][37]. Regarding the 13 C{ 1 H} NMR spectrum, the C(2) carbon of the benzothiazolyl moiety is observed at 176.0 ppm, which is significantly downfield compared to the corresponding carbon of free benzothiazole (153.8 ppm) [42], and thus confirms its metallation ( Figure S5) [23]. In addition, it is worth mentioning that the carbene carbon signal of 7 is downfield shifted (177.9 ppm) when compared to that of 3 (165.9 ppm [35]), which suggests a decrease in the Lewis acid character of the metallic center caused by an increase in the σ-donor ability of the ancillary ligand, [43][44][45][46]. This is similar to what is observed with the phenyl and methyl derivatives: [NiCpPh(IMes)] (181.2 ppm) [34] and [NiCpMe(IMes)] (187.4 ppm) [35].
To confirm the identity of 7, complex 3 was treated with a small excess of benzothiazole (1.2 equiv.) in the presence of potassium bis(trimethylsilyl)amide (KHMDS) as a base in toluene at room temperature (Scheme 3). The resulting complex was isolated in 80% yield as an air-stable greenbrown powder after work-up. Full characterization by 1 H and 13 C{ 1 H} NMR, HRMS spectroscopies and CHN microanalyses confirmed the expected formulation. Thus, for instance, the 1 H NMR spectrum of 7 no longer displays the H(2) proton of benzothiazole, but displays the H(5) and H(6) protons as two apparent triplets at 7.12 and 6.98 ppm, as seen in the spectra of the catalytic attempts (vide supra), and the H(4) and H(7) protons as two doublets at 7.58 and 7.51 ppm ( Figure S4). The Cp and IMes protons are found at values that are typical for NiCp(IMes) compounds [27][28][29][30][31][32][33][35][36][37]. Regarding the 13 C{ 1 H} NMR spectrum, the C(2) carbon of the benzothiazolyl moiety is observed at 176.0 ppm, which is significantly downfield compared to the corresponding carbon of free benzothiazole (153.8 ppm) [42], and thus confirms its metallation ( Figure S5) [23]. In addition, it is worth mentioning that the carbene carbon signal of 7 is downfield shifted (177.9 ppm) when compared to that of 3 (165.9 ppm [35]), which suggests a decrease in the Lewis acid character of the metallic center caused by an increase in the σ-donor ability of the ancillary ligand, [43][44][45][46]. This is similar to what is observed with the phenyl and methyl derivatives: [NiCpPh(IMes)] (181.2 ppm) [34] and [NiCpMe(IMes)] (187.4 ppm) [35].

Crystallographic Study of 7
The X-ray diffraction study of a single crystal of complex 7 corroborated the NMR data and confirmed the molecule's structure (Figure 2 and Appendix A). Significant bond distances and bond angles are given in Table 2 and crystallographic data and data collection parameters are listed in Table S1. Complex 7 crystallizes in the orthorhombic chiral space group P2 1 2 1 [47]. The Ni-C(2) distance is also significantly shorter than that observed in the only other fully characterized Ni-C(2)-benzothiazolyl complex (1.936(8) Å), that was just reported [23]. The C(1)-Ni-C(2) angle of 94.26 (10) [47]. Finally, when one takes into account the plane formed by the Cp centroid, C(1), and C(2), the nickel atom is almost in a planar environment ( Table 2, last entry), as is typically observed in similar two-legged piano-stool CpNi(NHC) complexes [27][28][29][30][31][32][33]35]. Table 2. Key bond distances (Å) and angles ( • ) of 7 with Esd's in parentheses.

Investigation of the Reactivity of the Cp* Complex 5
The little activity observed with the Cp* complex 5 (Table 1, entry 7) raised the question whether the observed coupling reaction goes through a benzothiazolyl complex similar to 7. To answer this question, complex 5 was treated with benzothiazole and KHMDS similarly to 3. A quick reaction occurred, but the corresponding benzothiazolyl complex 8 could only be isolated in 12% yield (Scheme 4) and we have been unable to obtain it analytically pure owing to its relative instability in solution that leads to insoluble materials and/or paramagnetic species. The metallation of benzothiazole was nevertheless confirmed by the absence of the H(2) proton in the 1 H NMR spectrum ( Figure S6) and the downfield shift of the C(2) carbon from 153.8 to 180.9 ppm in the 13 C{ 1 H} NMR spectrum ( Figure S7).

Investigation of the Reactivity of the Cp* Complex 5
The little activity observed with the Cp* complex 5 (Table 1, entry 7) raised the question whether the observed coupling reaction goes through a benzothiazolyl complex similar to 7. To answer this question, complex 5 was treated with benzothiazole and KHMDS similarly to 3. A quick reaction occurred, but the corresponding benzothiazolyl complex 8 could only be isolated in 12% yield (Scheme 4) and we have been unable to obtain it analytically pure owing to its relative instability in solution that leads to insoluble materials and/or paramagnetic species. The metallation of benzothiazole was nevertheless confirmed by the absence of the H(2) proton in the 1 H NMR spectrum ( Figure S6) and the downfield shift of the C(2) carbon from 153.8 to 180.9 ppm in the 13 C{ 1 H} NMR spectrum ( Figure S7). Complex 8 was then treated with 1.5 equiv. of iodobenzene in 1,4-dioxane at 140 °C for 16 h. The reaction led to a massive decomposition of the complex together with a small amount of the expected coupling product (<15% of the identified species) as inferred from the 1 H NMR analysis of the crude reaction mixture that shows a very complex mixture. This illustrates the less stable (or more reactive) character of the Cp* derivative 8, when compared to its Cp analogue 7, and suggests the possible involvement of such a benzothiazolyl complex in the coupling reaction [23,[39][40][41], provided that it does not constitute a potential energy well like the Cp derivative 7.
A possible explanation for the enhanced reactivity of 8 may come from both its more electronrich character, as shown by its downfield shifted carbene carbon in the 13 C { 1 H} NMR spectrum: 187.4 ppm in 8 vs. 177.9 ppm in 7 [43][44][45][46], and its more significant steric crowding. Indeed, in a hypothetic Ni(II)/Ni(IV) catalytic cycle, as proposed by Chatani et al. for a related arylation reaction of Csp 2 -H bonds with aryl iodides [48], the presence of a bulky electron-donating ligand such as Cp* may (i) favor the oxidative addition of the aryl halide through electronic donation, and (ii) subsequently Complex 8 was then treated with 1.5 equiv. of iodobenzene in 1,4-dioxane at 140 • C for 16 h. The reaction led to a massive decomposition of the complex together with a small amount of the expected coupling product (<15% of the identified species) as inferred from the 1 H NMR analysis of the crude reaction mixture that shows a very complex mixture. This illustrates the less stable (or more reactive) character of the Cp* derivative 8, when compared to its Cp analogue 7, and suggests the possible involvement of such a benzothiazolyl complex in the coupling reaction [23,[39][40][41], provided that it does not constitute a potential energy well like the Cp derivative 7.
Catalysts 2019, 9, 76 6 of 10 A possible explanation for the enhanced reactivity of 8 may come from both its more electron-rich character, as shown by its downfield shifted carbene carbon in the 13 C { 1 H} NMR spectrum: 187.4 ppm in 8 vs. 177.9 ppm in 7 [43][44][45][46], and its more significant steric crowding. Indeed, in a hypothetic Ni(II)/Ni(IV) catalytic cycle, as proposed by Chatani et al. for a related arylation reaction of Csp 2 -H bonds with aryl iodides [48], the presence of a bulky electron-donating ligand such as Cp* may (i) favor the oxidative addition of the aryl halide through electronic donation, and (ii) subsequently enhance the reductive elimination of the coupling product due to its steric bulkiness [49]. Further developments of this family of complexes for similar cross-couplings might therefore privilege species with more electron-donating and/or more bulky ligands [50].

General Comments
All reactions were carried out using standard Schlenk procedures under an atmosphere of dry argon. Solvents were dried and distilled under argon. Solution NMR spectra were recorded at 298 K on a Bruker Avance I 300 MHz spectrometer operating at 300.13 MHz for 1 H and at 75.47 for 13 C{ 1 H}. A DEPT 13 C spectrum was recorded for complex 7 to ease the 13 C signals assignment. The chemical shifts are referenced to the residual deuterated or 13 C solvent peaks. Chemical shifts (δ) and coupling constants (J) are given in ppm and Hz, respectively. GC analyses were carried out with n-dodecane as an internal standard, using an Agilent 7820A instrument equipped with a HP-5 column (cross-linked 5% phenyl silicone gum, 30 m × 0.32 mm × 0.25 µm). Conversion was determined by considering instrument response factors. The GC conditions were: (i) 50 • C for 5 min, (ii) increase in temperature at a rate of 10 • C/min until 150 • C, (iii) isotherm for 5 min, and (iv) temperature increase at 20 • C/min until 240 • C; retention times: iodobenzene: 8.7 min; dodecane 11.6 min; benzothiazole: 12.0; 2-phenylbenzo[d]thiazole: 23.4 min. The retention time of 2-phenylbenzo[d]thiazole was determined with a pure sample of the latter obtained by using 1 as catalyst (Scheme 1) [24]. Elemental analyses were performed by the Service d'Analyses, de Mesures Physiques et de Spectroscopie Optique, Institut de Chimie, UMR 7177, Université de Strasbourg. High-resolution mass spectra were recorded on a Bruker micrOTOF mass spectrometer by the Service the Spectrométrie de Masse, Institut de Chimie, UMR 7177, Université de Strasbourg. Benzothiazole, haloarenes and n-dodecane were distilled and stored under argon before use. [NiCpCl(IMes)] (3) [35,36], [NiCpCl(IPr)] (4) [27,37], [NiCp*Cl(IMes)] (5) [38], and [NiCp(NCMe)(IMes)](PF 6 ) (6) [29] were prepared according to the published methods.

Synthesis of [NiCp(C 7 H 4 NS)(IMes)] (7)
KHMDS (1.2 mL, 0.600 mmol, 0.5 M in toluene) was added to a solution of 3 (200 mg, 0.431 mmol) and benzothiazole (56 µL, 0.514 mmol) in toluene (12 mL) at room temperature, resulting in a very rapid change of color from red to green. After 12 h, the reaction medium was filtered through a Celite pad and concentrated in vacuo to give a brownish powder that was washed with pentane (3 × 10 mL). Re-dissolution of this solid in toluene (10 mL) and THF (0.5 mL) and filtration through neutral alumina with toluene and toluene/THF (20:1) as successive eluents then afforded a green solution that was evaporated to dryness to give 7 as a green-brown powder (193 mg, 0.343 mmol, 80%). Anal. Calcd for C 33 13

Synthesis of [NiCp*(C 7 H 4 NS)(IMes)] (8)
KHMDS (0.9 mL, 0.450 mmol, 0.5 M in toluene) was added to a solution of 5 (236 mg, 0.447 mmol) and benzothiazole (48 µL, 0.442 mmol) in toluene (12 mL) at room temperature, resulting in a very rapid change of color from red to olive. After 2 h, the volatiles were evaporated under vacuum to give a brown residue that was extracted with toluene and loaded on the top an alumina pad (4 × 3 cm) that was eluted (i) with toluene to yield a yellow fraction, and (ii) with a toluene/THF mixture (20:1) to yield an olive fraction. The latter was then evaporated to dryness to give 8 as an olive solid (34 mg, 0.0538 mmol, 12%). 1

Crystallographic Studies
Single crystals of 7 suitable for X-ray diffraction studies were harvested from a batch of crystals obtained at room temperature from a toluene/pentane (1:3) solution. Diffraction data were collected at 173(2) K on a Bruker APEX II DUO Kappa CCD area detector diffractometer equipped with an Oxford Cryosystem liquid N 2 device using Mo-Kα radiation (λ = 0.71073 Å). The crystal-detector distance was 38 mm. The cell parameters were determined (APEX2 software [51]) from reflections taken from three sets of twelve frames, each at ten seconds exposure. The structures were solved using direct methods with SHELXS-2014 and refined against F 2 for all reflections using the SHELXL-2014 software [52]. A semi-empirical absorption correction was applied using SADABS [53] in APEX2 [51]: transmission factors: T min /T max = 0.7423/0.9540. All non-hydrogen atoms were refined with anisotropic displacement parameters, using weighted full-matrix least-squares on F 2 . Hydrogen atoms were included in calculated positions and treated as riding atoms using SHELXL default parameters. A summary of crystal data, data collection parameters, and structure refinements is given in Table S1.

Conclusions
In summary, we have shown that apart from the Cp* derivative 5, which shows a little activity, all other tested half-sandwich Ni(NHC) of general formula [NiCpL(NHC)] (+) complexes are incapable of catalyzing the direct coupling of benzothiazole with aryl halides in the presence of an alkoxide as a base. They instead form a C(2)-metallated benzothiazolyl complex that constitutes a potential energy well that quenches all further reactivity. Although benzothiazolyl complexes are often proposed as possible intermediates in such biaryl couplings, the isolated complex, [NiCp(C 7 H 4 NS)(IMes)] (7), is to our knowledge a very rare example of fully characterized C(2)-benzothiazolyl-nickel complex.