Betaine–N‐Heterocyclic Carbene Interconversions of Quinazolin‐4‐One Imidazolium Mesomeric Betaines. Sulfur, Selenium, and Borane Adduct Formation

Reaction of N-alkylated imidazoles with 2-chloro-4quinazolinone gave mesomeric betaines, 2-(1-alkyl-1H-imidazolium-3-yl)quinazolin-4-olates, for which three tautomeric forms of N-heterocyclic carbenes (NHCs) can be formulated, in addition to an anionic NHC after deprotonation. The NHC tautomers were trapped with sulfur, selenium, triethylborane, and triphenylborane as thiones, selenones and borane adducts, respectively. We obtained two isomers of the cyclic borane adducts, diazaboroloquinazolinones with [1,5-a] and [5,1-b]-type fusion between the quinazolinone and the diazaborole rings.


Introduction
Since the first isolation of a stable N-heterocyclic carbene (NHC) by Arduengo in 1991, [1] this class of compounds has developed considerably and nowadays NHCs are ubiquitous in organic as well as inorganic chemistry. They are widely applied in catalysis, organocatalysis, and complex chemistry. The significance of Nheterocyclic carbenes and of their anionic derivatives is impressively demonstrated by numerous books, [2] monographs, [3] They correspond to two different NHC tautomers and to the anionic NHC derived thereof. The third NHC tautomer was trapped as a non-cyclic adduct with tris(pentafluorophenyl)borane by coordination to the quinazoline oxygen atom. 2D 1 H-15 N HMBC experiments of 15 N-labeled quinazolinone fragments, quantitative measurements of long-range 1 H-15 N coupling constants (J HN ), and five X-ray single crystal analyses have been carried out for the structure elucidations and to gain insight into the NMR spectroscopic properties of these compounds. and review articles, [4] the latest of which reflect the broad applicability of this class of compounds. They deal with main group element adducts, [5] NHCs in materials chemistry, [6] NHCs as ligands in cross-couplings [7] and in rhodium-catalyzed reactions [8] as well as copper, nickel, and cobalt complexes. [9] The enhancement of the σ-donating properties of N-heterocyclic carbenes was one of the initial goals of the design of a broad variety of interesting structures, resulting in strong donors such as cyclic alkyl amino carbenes (CAACs) [10] and others. However, strong NHC donation can also have divergent effects in transition-metal catalysis. [11] It has also been shown that the properties of N-heterocyclic carbenes as well as of their anionic derivatives are not only governed by the donicity of their characteristic σ-lone pair and the σ-framework of the parent heterocycle, but also by their π-electronic architecture. As a result, the carbene properties depend significantly on the type of conjugation in the NHC framework. [12] For example, the negative charge of the anionic N-heterocyclic carbene 2 [13] (Scheme 1) derived from zwitterion 1 is not delocalized in terms of resonance. It can be classified as isolated anionic N-heterocyclic carbene. By contrast, the mesomeric betaines 3 and the corresponding NHC 4 (imidazol-2-yliden-4-olates, X = O [14] and imidazol-2-yliden-4aminides, X = NR [15] ) delocalize their negative charges within the π-electron system. The same is true for the sydnone carbenes 6 (X = O) [16] and their sydnone imine derivatives (X = NR) [17] generated from mesoionic precursors 5, as well as for the ylide carbenes possessing the partial structure 8 derived from ylides 7. [18] All anionic N-heterocyclic carbenes obtained by formal deprotonation from these mesomeric betaines possess conjugated π-electronic backbones with delocalized negative charges which can be located on the carbene carbon atom itself according to the rules of resonance. Consequently, considerable atomic orbital coefficients of the highest occupied molecular orbitals (HOMO) are localized on these positions. Thus, the π-acceptor properties of the carbene carbon atoms are expected to change considerably in comparison to the reference imidazol-2-ylidene system. By contrast, the NHC 10 [19] derived from mesomeric betaine 9 [20] is cross-conjugated, as its anionic partial structure is π-electronically separated from the carbene center. Therefore the influence of the π-electronic backbone is considerably diminished in comparison to conjugated systems. The influence of substituent, field and resonance effects on the ease of N-heterocyclic carbene formation from imidazolium rings [21] and a quantitative analysis of factors influencing the ease of formation as well as the σ-bonding strength of selected oxa-and thia-N-heterocyclic carbenes [22] have been calculated and thus give an additional impetus for further progress in this field of chemistry. Scheme 1. Examples of a zwitterion (1) and of mesomeric betaines (3,5,7,9) as well as their N-heterocyclic carbenes.
Herein, we report on the syntheses of our target ring system and carbene trapping reactions with sulfur, selenium, triethylborane and triphenylborane. σ-Donicities as well as π-properties have been estimated by means of 1 J CSe and 1 J CH coupling constants and 77 Se NMR chemical shifts. For structure elucidations of the boron adducts we used a new approach based on the analysis of long-range J HN -couplings in 2D 1 H-15 N spectra of 15 N-labeled samples. To the best of our knowledge, the boron adducts are the first representatives of new heterocyclic ring systems.

Syntheses
The syntheses of the target molecules was smoothly accomplished by C-N bond formation between 2-chloroquinazolin-4one 14 and the N-alkylated imidazole derivatives 15a-d (Scheme 3). Imidazole 15a was dissolved in 1,2-dichlorobenzene (1,2-DCB), whereas all liquid azoles 15b-d reacted without additional solvent. In the latter cases the mesomeric betaines 13 b b-d were formed in one step, whereas 15a gave the salt 16 which was converted into the betaine 13 b a by the anion exchange resin Amberlite IRA-400 in its hydroxide form (the index "b" stands for "mesomeric betaine"). On treatment of the 15 N-enriched chloroquinazolinone *14 ( 15 N, 95 %) with the imidazoles 15a,b,d the labeled salt *16 and the betaines *13 b b,d were obtained, and *16 was then converted into *13 b a in analogy to 16. Details of the synthesis of *14 starting from 1H-benzo[d] [1,3]oxazine-2,4-dione and 15 N-ammonium chloride ( 15 N, 95 %) are given in the Supporting Information. The 1 H NMR signal of H2′ imidazole is diagnostic for the betaine formation, as 16/*16 showed a signal at 10.31 ppm, whereas the corresponding signals of the betaines 13 b a-d/*13 b a-c were detected between 10.14 ppm and 9.88 ppm in [D 6 ]DMSO, respectively. No traces of the carbene tautomers 13 c a-d/*13 c a-c (see Scheme 4) were detectable under these conditions (the index "c" stands for "N-heterocyclic carbene"). The selective incorporation of a 15 N label into the N3 position of the quinazoline fragment of the mesomeric betaines *13 b a,b,d were confirmed by a characteristic pattern of 13 C-15 N3 coupling con-N abundance) were detected in the 2D 1 H-15 N HMBC NMR spectra, so that we were able to unambiguously assign all signals of the betaines 13 b a-d/*13 b a,b,d to their corresponding nitrogen atoms. The 15 N1 and 15 N3 resonances were observed in the spectral ranges of 199-203 ppm and 208-216 ppm, respectively (see Table S2 and 2D 1 H-15 N spectra, Supporting Information).

Classification and Calculations of the Betaines and Carbenes
The mesomeric betaines 13 b a-d belong to the class of crossconjugated mesomeric betaines (CCMB), as the resonance forms show no common atoms for either charge within the common π-electron system [34] (Scheme 4). Four different tautomers of 13 b a-d can be formulated, three of which are the Nheterocyclic carbenes 13 c a-d-I-III. The most stable conformers of 13 b b and 13 c b-I were calculated to be the syn-conformers as shown (ΔE = 3.6 and 54.5 kJ mol -1 , respectively), whereas the anti-conformers are more stable for the case of the tautomers 13 c b-II and 13 c b-III (ΔE = 68.3 and only 0.3 kJ mol -1 , respectively) according to DFT calculations (PBE0, 6-31G*). Among these tautomers, the betaine tautomer 13 b b is the most stable, followed by NHC tautomer I (ΔE = 8.7 kJ mol -1 ). The anionic N-heterocyclic carbenes 13 ac a-d constitute the deprotonated form of the aforementioned species (the index "ac" stands for "anionic N-heterocyclic carbene"). They delocalize their negative charge exclusively within the quinazolinonide moiety according to the rules of resonance. The anti-conformer of 13 ac b was found to be 7.8 kJ mol -1 more stable than its syn-conformer in vacuo.
The J HC coupling constants of carbene precursors 13 b a-d can be taken as a measure of the σ-donor strength of the corresponding NHCs. [35] We measured J H2′-C2′ coupling constants between 225.7 Hz (13 b c) and 226.3 Hz (13 b a) (Table S3 and Fig. S3, Supporting Information) which resemble the value of 1,3-dimesitylimidazol-2-ylidene (J H2′-C2′ = 225 Hz). A comparison between 13 b a-d and the salt 16 can rule out contributions of intramolecular hydrogen bonds between C2′H and N3 in solution which might cause slightly increased values for the 1 J H2′-C2′ coupling constants, [36] as the values of the betaines and the salt are very similar. Thus, a coupling constant of 227. 5 Hz was detected in 16, which cannot form the aforementioned hydrogen bond.
The weak electron-donating effect of the anionic substituent is also well reflected in the calculated frontier orbitals of the model compound 13 b b (Figure 1), because the cationic fragment is joined via a nodal position of the highest occupied molecular orbital (HOMO) to the anionic fragment. This is characteristic of cross-conjugated systems. The HOMO of the NHC tautomer 13 c b-I is a π-orbital with considerable atomic orbital coefficients in the quinazolinonide substituent. As the system is planar in vacuo according to the calculation some small coefficients on N1′ and the carbene carbon atom C2′ have also been found. The HOMO-1 shows the characteristic σ-lone pair of the NHC, and its lowest unoccupied molecular orbital (LUMO) possesses a considerable atomic orbital coefficient on the carbene carbon atom. The tautomers 13 c b-II and 13 c b-III differ slightly in their frontier orbital geometries and energies (see Fig. S7, Supporting Information). The HOMO of the anionic NHC 13 ac b resembles the HOMO of the betaine with respect to its geometry. Interestingly, the HOMO-1 combines the σ-lone pair of the NHC with the σ-framework of the anionic fragment of the quin-  azolinonide substituent including the free electron pairs of the nitrogen and oxygen atoms. The type of conjugation is also well reflected in the HOMO/ LUMO energies. We think that the E σ energy of 13 ac b is lower than those of anionic conjugated N-heterocyclic carbenes such as sydnone carbenes [16] or the extremely π-electron-rich conjugated molsidomine carbene, [17] which we reported earlier, due to the cross-conjugation which induces a π-electronic isolation of the negatively charged substituent with respect to the frontier orbitals. An additional reason might be the better mesomeric stabilization of the anionic charge. A comparison of the HOMO/LUMO energies of the cationic NHC derived from imidazo [4,5-b]pyridinium, [37] of the 13 series reported here, of the reference NHC 1,3-dimethylimidazol-2-ylidene, and the conjugated anionic sydnone carbene [16] is displayed in Figure 2. These examples of NHCs cover the range from extremely πelectron poor to extremely π-electron rich.

Betaine-Carbene Transformations and Trapping Reactions
On treatment of the mesomeric betaines 13 b a-d with sulfur and selenium, respectively, the adducts 17a-d and 18a-d of the tautomeric carbenes 13 c a-d-I were obtained in 18-72 % yield (Scheme 5). The 77 Se NMR chemical shifts have been first utilized by Ganter et al. to determine the π-acceptor strengths of NHCs within the adducts [38] and the method has been applied to numerous NHCs since then. [39] The selenium atoms appear as singlets between 100.57 ppm (18a), 104.74 ppm (18c) and 120.85 ppm (18b) in the 77 Se NMR spectra which is indicative of weak π-acceptor capabilities. The values are similar to those of 1,3-dimesitylimidazol-2-ylidene (δ Se = 116 ppm). [35] The corresponding 1 J CSe coupling constants were found to be 237 Hz (18a), 236 Hz (18b), and 237 Hz (18c) (  . These values are indicative of σ-donicities which resemble those of 1,3-di(isopropylphenyl)-4,5-dichloro-imidazol-2-ylidene (239 Hz). [35] We were able to grow single crystals of 17a and to perform an X-ray crystal structure analysis the molecular drawing of which is shown in the Supporting Information (Fig. S8, Supporting Information). The analysis of this structure revealed an interatomic distance between H3 and the sulfur in position 2′ of 2.205 Å which is significantly smaller than the sum of the van der Waals radii of the corresponding atoms (≈ 3 Å). This indicates the formation of a N3-H···S=C2′ hydrogen bond in the solid state. However, the moderate downfield-shift of the H3 resonances frequencies observed for the case of the sulfur and selenium adducts [δ H between 13.71 (18a) and 14.13 (17b) ppm] in comparison to the corresponding value of compound *14 (13.27 ppm), where such H-bonding is not possible, cannot confirm significant hydrogen bonds in solution. The presence of hydrogen bonds influences δ Se values. We think that their influences are negligible here in view of the very large chemical shift range from 0 to 850 ppm [35] of 77 Se resonance frequencies in selenium-NHC adducts. To the best of our knowledge they are first representatives of new heterocyclic ring systems and are formal trapping adducts of the anionic NHC 13 ac a-d. The formation of the borane adducts 19a-d and 20c,d was confirmed by the appearance of signals in the range from 1.1 ppm to -0.8 ppm in the 1D 11 B NMR spectra, and of 21a-d and 22c,d between -1.80 ppm and -2.62 ppm which is the typical range of 11 B resonance frequencies of carbene adducts. [28] The resonances of the 11 B nuclei and signals of the neighbouring 13 C nuclei in the 2′ and 1′′ positions were significantly broadened, probably due to the presence of the negative partial charge of the boron atom as indicated by the alternative representations shown in Scheme 5. This made the observation of 11 B J-couplings impossible. The structure of the compounds 19a-d and 20c,d, however, was unambiguously elucidated by analysis of the J HN -couplings in the 2D 1 H-15 N HMBC NMR experiments which were recorded for samples with natural isotopic abundance of 15 N nuclei in [D 6 ]DMSO solution (see 2D 1 H-15 N HMBC spectra, Supporting Information). The spectra of the isomers 20c,d showed two cross-peaks corresponding to the vicinal 3 J H8-N1 and 3 J H1′′-N1 couplings which confirm the cyclization via N1 ( Figure 3). The nitrogen atoms of the quinazoline moiety of 19a-d were first assigned by their 1 H-15 N coupling constants, then the 3 J H1′′-N3 and 3 J H8-N1 couplings confirmed their [1,5-a]-fusion.   As recently reviewed, [40] selective 15 N-labeling is highly efficient for structure elucidations. As the absence of hydrogen atoms attached to C1′′ of 21 and 22 prevented cross-peaks in HMBC measurements, we prepared *21a,b,d and *22d possess-ing 15 N labels at the N3 positions from *13a,b,d ( Figure 5). Thus, the detection of long-range 1 H-15 N3 interactions in the 2D 1 H-15 N HMBC spectra and quantitative measurements of the corresponding J HN3 ( Figures S5 and S6, Supporting Information) as well as of the diagnostic 13 C-15 N3 J-coupling constants was possible ( Fig. S1, Supporting Information).  [41] In the parent betaines 13 b a-d the 15 N1 and 15 N3 nuclei resonated in regions around 200 and 215 ppm, respectively. It is interesting to note that the cyclization via the N3 atom (compounds 19ad and 21a-d) does not influence significantly the 15 N1 chemical shifts, but induces an upfield shift of approximately 40 ppm of the 15 N3 atoms to ca. 175 ppm (see Fig. S2 and Table S2, Supporting Information). Contrary to that, the cyclization through the N1 atom in compounds 20c,d and 22c,d does not change the chemical shifts of the 15 N3 atom, whereas the signals of 15 N1 atom shift upfield by ≈ 50 ppm to approximately 150 ppm. The structures of the isomeric adducts 21a and 22d were also proved by X-ray crystallographic analyses ( Figure 6). Suitable single crystals of 21a and 22d were obtained by slow evaporation of concentrated solutions in acetonitrile. Compound 21a crystallized with one molecule of acetonitrile in the triclinic space group P1, whereas 22d crystallized in the monoclinic space group P2 1 /c. The B-C1 carbene bond lengths (crystallographic numbering) were determined to be 1.643(2) Å (21a) and 1.619(3) Å (22d), respectively, which is slightly shorter than those of other boron adducts. [28c] The bond lengths between the boron atom and the nitrogen atom N3 and N1 in 21a and 22d were found to be 1.618(2) and 1.620(3) Å, respectively. The torsion angles between imidazole and the quin-azoline fragment C1-N2-C2-N1 (21a) and N1-C2-N3-C4 (22d) were determined to be -179.08 (14)°and -1.7(3)°. These data confirmed that the quinazoline, diazaborole, and imidazole fragments of 21a and 22d are almost planar. Figure 6. ORTEP diagrams of the X-ray structures of compounds 21a (a, above) and 22d (b, below). Finally, we were also able to form adducts via the oxygen atom of the betaines. Thus, tris(pentafluorophenyl)borane in dioxane at room temperature reacted with 13 b a-c to give the borates 23a-c in 56 %, 48 % and 20 % yields, respectively (Scheme 6).
The attachment of the pentafluorophenyl substituent was confirmed by a 2D 1 H-19 F HOESY spectrum measured for compound 23b. The spectrum revealed dipolar interactions between the 19 F2′′ nuclei of the pentafluorophenyl and 1 H5 as well as 1 H4′, and overlapped 1 H6/ 1 H5′ signals of the heterocyclic moiety (Figure 7 and see Figure S135, Supporting Information). The 15 N chemical shifts provide additional information about the structure of 23b. In this case the 15 N1 and 15 N3 resonances demonstrated only weak downfield shifts relative to the parent betaine 13 b b. They have chemical shifts of ≈ 224 ppm and ≈ 220 ppm, respectively (Table S2 and Fig. S2, Supporting Information). The resonance frequencies of N1′ and N3′ of the imidazole ring also remained essentially unchanged. Thus, the attachment of the boron substituent does not affect the nitrogen atoms, keeping only one possibility of attachment through the oxygen atom.

Conclusions
The mesomeric betaines 2-(1-alkyl-1H-imidazolium-3-yl)quinazolin-4-olates are cross-conjugated and crypto-N-heterocyclic carbenes. The latter can be formulated as three different tautomers or as anionic N-heterocyclic carbene after deprotonation. Imidazole-2-thiones and imidazole-2-selenones were obtained on reaction of sulfur and selenium, respectively, with the betaines, which behave as N-heterocyclic carbenes under these conditions. The usage of triethylborane and triphenylborane led to new cyclic borane adducts, imidazo[2′,1′:3,4][1,4,2]diazaborolo-  19 F HOESY spectra turned out to be useful for the identification of noncyclic adducts containing pentafluorophenyl groups. The σ-donating and π-accepting properties of the N-heterocyclic carbenes were estimated by analysis of 1 J CSe and 1 J HC coupling constants as well 77 Se resonance frequencies. In accordance with their classification as cross-conjugated systems and in contrast to conjugated systems, the anionic substituent takes only a weak influence on the characteristics of the corresponding NHCs. These results supplement on the one hand our knowledge about the intersection of the two substance classes of N-heterocyclic carbenes and mesomeric betaines which are crypto-NHCs depending on their type of conjugation, and on the other hand our knowledge about boron adducts of NHCs. [45]

Experimental Section
All reactions were carried out under an atmosphere of nitrogen in flame or oven-dried glassware. All chemicals were purchased and used without further purification unless otherwise mentioned. Anhydrous solvents were dried according to standard procedures before usage. Melting points are uncorrected and were determined in an apparatus according to Dr. Tottoli (Büchi). The ATR-IR spectra were obtained on a Bruker Alpha in the range of 400 to 4000 cm -1 . 1 H, 11 B, 13 C, 15 N, 19 F and 77 Se NMR spectra were measured in [D 6 ]DMSO solution using Bruker AVANCE-II-400 or Bruker NEO 600 spectrometers equipped with room temperature broadband probes, or using a Bruker AVANCE-700 spectrometer equipped with a triple-resonance ( 1 H, 13 C, 15 N) room-temperature probe. 1 H chemical shifts were referenced to the DMSO signal which appeared at 2.50 ppm. Chemical shifts of 11 B, 13 C, 15 N, 19 F, and 77 Se nuclei were referenced indirectly relative to boron trifluoride etherate, Me 4 Si, liquid ammonium, CCl 3 F and Me 2 Se, respectively. Multiplicities are described by using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. The assignment of all 1 H and 13 C resonances was achieved using gradient enhanced versions of 2D NMR 1 H-13 C HSQC, and 1 H-13 C HMBC experiments. The assignment of 15 N atoms (labeled or at natural abundance) was based on 2D 1 H-15 N HMBC experiments. The measurements of J H-C , J H-N , J C-N and J C-Se coupling constants are described in the Supporting Information. The mass spectra (ESIMS) were measured with a Varian 320 MS Triple Quad GC/MS/MS (EIMS) or with an Agilent LCMSD series HP 1100 with APIES at fragmentor voltages as indicated. Samples were sprayed from MeOH at 4000 V capillary voltage and fragmentor voltages of 30 V unless otherwise noted. The HRMS spectra were obtained with a Bruker Impact II, a Bruker Daltonik Tesla-Fourier transform-ion cyclotron resonance mass spectrometer, or with a Waters Micromass LCT with the direct inlet. Chromatography: The reactions were traced by thin layer chromatography with silica gel 60 (F254, company MERCK KGAA). For the detection of substances, quenching was used at either 254 nm or 366 nm with a mercury lamp. The preparative column chroma-tography was conducted through silica gel 60 (230 400 mesh) of the company MERCK KGAA. Yields are not optimized.

Crystal Structure Determinations
The X-ray diffraction data of the compounds 17a, 19b, 21a and 22d were collected on a Xcalibur S diffractometer with Mo-K α radiation (λ = 0.71073 Å, graphite monochromator, ω/2θ-scanning technique). Unit cell parameters were refined using all collected spots after the integration process. The structures were solved by direct methods that were implemented in the SHELXS-97 program. [46] The refinements were carried out through full-matrix anisotropic leastsquares methods on F 2 for all reflections of the non-H atoms using the SHELXL-97 program. [47] The single-crystal X-ray diffraction studies of compound 23b were carried out on a Bruker SMART APEX II diffractometer equipped with a CCD detector (Mo-K α , λ = 0.71073 Å, graphite monochromator). Semiempirical absorption correction was applied. [48] The structures were solved by direct methods and refined by the full-matrix least-squares with anisotropic displacement parameters using the SHELX-2014 program package. [49] The hydrogen atoms of the ligands were positioned geometrically and refined using the riding model.

Calculations
All density-functional theory (DFT)-calculations were carried out applying the current Spartan Software (Spartan'18, Wavefunction, Inc., Irvine, CA. Available from: http://www.wavefun.com) running on an Intel® Core TM i7-6950X decacore system equipped with 64 GB RAM main memory and sufficient solid-state disc space. MM2 optimized structures were used as starting geometries. Complete geometry calculations were performed with the PBE0 density functional and the implemented 6-31G* basis set in order to allow for comparison with previous results. All final structures were proven to be true minima by the absence of imaginary frequencies.

Synthesis
Compound 14 was prepared according to previously published protocols. [50] The synthesis of *14 is presented in the Supporting Information.

2-(1-Benzyl-1H-imidazolium-3-yl)quinazolin-4-olate (13 b a):
A 150 mL portion of the anion-exchange resin Amberlite IRA-400 was filled into a column (height: 16 cm, diameter: 3 cm) and washed with 2 L of water. Then 100 mL of a 5 % hydrochloric acid solution was added and remained in the column for 2 h. The hydrochloric acid was then rinsed out with water until pH 7 was reached. 100 mL of a 5 % aqueous solution of sodium hydroxide was added and remained in the column for 2 h. Then the base was rinsed out with water until pH = 7 was reached. Then, samples of salts 16 (0.677 g, 2.0 mmol) in 60 mL of water were added on the resin. After that, the resulting betaine was extracted with ethyl acetate and solvent was evaporated in vacuo. Yield 0.508 g, 84 %, colorless solid, m.p. > 252°C (dec.

General Procedure for the Synthesis of the Betaines 13 b b, 13 b d:
Under an inert atmosphere a mixture of 2-chloroquinazolin-4(3H)one (180 mg, 1.0 mmol) and 2 equiv. excess of corresponding imidazoles (2.0 mmol) was stirred at 100-105°C for 2 h without solvent.
After stirring mixture was cooled to r.t., added CHCl 3 (13 b b) or dioxane (13 b d), then the resulting precipitates were filtered off, washed with a small amount of CHCl 3 (13 b b) or dioxane (13 b d) and dried. (13