LiOtBu-Promoted Intramolecular 1,3-Dipolar Cycloaddition of the 2′-Alkynyl-biaryl-2-aldehyde N-Tosylhydrazones Approach to 3-Substituted 1H-Dibenzo[e,g]indazoles

A two-step, one-pot synthesis of 3-substituted 1H-dibenzo[e,g]indazoles in good to high yields via a LiOtBu-promoted intramolecular 1,3-dipolar cyclization of 2′-alkynyl-biaryl-2-aldehyde N-tosylhydrazones was developed. The N-Ts-hydrazones used were prepared in situ via the reactions of 2′-alkynyl-biaryl-2-aldehydes and TsNHNH2 (p-methylbenzenesulfonohydrazide). Two types of signals related to the hydrogen bonds, forming in several products, were observed in the 1H NMR spectra recorded in DMSO-d6, assigned to N-H bonds in their dimeric species of product and tautomer.

Since the synthesis of 2H-dibenzo[e,g]indazoles has already been reported [28], in the present work, we opted for a synthetic method towards 1H-dibenzo[e,g]indazoles, providing more possibilities of indazole-based derivatives in a further exploration of pharmaceutical molecules or larger polycyclic aromatic compounds (PACs).
mized to a one-pot two-steps manner starting from 2′-alkynyl-biaryl-2-aldehydes (1) (Scheme 1c).In addition, in order to explain the observed two types of N-H signals in the 1 H NMR spectra in , the formation of dimeric species is proposed, which is supported by the X-ray structure of one product with the studies of DFT (density functional theory) calculations using the Gaussian 09 program [34] with an SMD solvation model [35].
Based on our previous studies on the use of N-tosylhydrazones in cyclizations [31][32][33], herein we report a one-pot synthetic method towards 3-substituted 1H-dibenzo[e,g]indazoles (2) from 2 ′ -alkynyl-biaryl-2-aldehyde N-tosylhydrazones, which was then optimized to a one-pot two-steps manner starting from 2 ′ -alkynyl-biaryl-2-aldehydes (1) (Scheme 1c).In addition, in order to explain the observed two types of N-H signals in the 1 H NMR spectra in DMSO-d 6 , the formation of dimeric species is proposed, which is supported by the X-ray structure of one product with the studies of DFT (density functional theory) calculations using the Gaussian 09 program [34] with an SMD solvation model [35].

Optimization of Model Reaction Conditions
Our investigations started from hydrazone 1a ′ , easily available from biarylaldehyde 1a and TsNHNH 2 (p-methylbenzenesulfonohydrazide) in methanol at room temperature.When the reaction of hydrazone 1a ′ (1.0 equiv.)and LiO t Bu (1.5 equiv.) in tetrahydrofuran (THF) was heated at 100 • C for 2 h, 3-phenyl-1H-dibenzo[e,g]indazole (2a) could be isolated in an 89% yield (Table 1, entry 1).When the temperature was progressively diminished at 50 • C, 45 • C, 35 • C, or 25 • C, the yields of 2a did not significantly decrease except for 25 • C (Table 1, entries [2][3][4][5].Repeating the reaction in THF at 45 • C for 1 h, the yield of 2a could be maintained in an 88% yield (Table 1, entry 6).Since hydrazone 1a ′ was prepared in methanol, we then examined the reaction of hydrazone 1a ′ in this solvent, rather than in THF, but the yield of 2a decreased to 68% (   cedure 1a → 2a.It was found that 1a could be totally converted into hydrazone 1a′ after 1 h (TLC monitoring).Moreover, when LiO t Bu (1.5 equiv.)and 2.5 mL of THF were added to the reaction mixture of entry 6, 2a could be obtained in an 88% yield after additional heating for 1 h.We also tried a one-step process at 45 °C: by adding TsNHNH2 and LiO t Bu at the same time, 79% of 2a could be acquired.Thus, the one-pot/two-step process in entry 6 was considered as the optimized condition.We also examined the formation of 2a from 1a using other inorganic alkali, such as NaO t Bu, KO t Bu, Li2CO3, Na2CO3, K2CO3, and Cs2CO3.As shown in Table 2, the use of NaO t Bu and KO t Bu resulted in the formation of 2a in 81% and 85% yields, respectively (entries 2 and 3), similar to the yield of LiO t Bu (entry 1).However, in the presence of Li2CO3, Na2CO3, K2CO3, and Cs2CO3, 2a only formed in 9-14% yields (entries [4][5][6][7].These results support the proposed mechanism depicted in Scheme 2 (vide infra), in which a tert-butoxide anion ( t BuO − ) made a main contribution to the intramolecular cyclization by promoting the formation of the diazo zwitterion A.  Therefore, the condensation between biarylaldehyde 1a and TsNHNH 2 in THF at 45 • C was further examined to explore the possibility of developing a two-step, one-pot procedure 1a → 2a.It was found that 1a could be totally converted into hydrazone 1a ′ after 1 h (TLC monitoring).Moreover, when LiO t Bu (1.5 equiv.)and 2.5 mL of THF were added to the reaction mixture of entry 6, 2a could be obtained in an 88% yield after additional heating for 1 h.We also tried a one-step process at 45 • C: by adding TsNHNH 2 and LiO t Bu at the same time, 79% of 2a could be acquired.Thus, the one-pot/two-step process in entry 6 was considered as the optimized condition.
We also examined the formation of 2a from 1a using other inorganic alkali, such as NaO t Bu, KO t Bu, Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 .As shown in Table 2, the use of NaO t Bu and KO t Bu resulted in the formation of 2a in 81% and 85% yields, respectively (entries 2 and 3), similar to the yield of LiO t Bu (entry 1).However, in the presence of Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 , 2a only formed in 9-14% yields (entries [4][5][6][7].These results support the proposed mechanism depicted in Scheme 2 (vide infra), in which a tert-butoxide anion ( t BuO − ) made a main contribution to the intramolecular cyclization by promoting the formation of the diazo zwitterion A. a Reaction conditions: 1a (1.0 mmol), TsNHNH2 (1.1 equiv.) in 5.0 mL of THF at 45 °C for 1 h, then base (1.5 equiv.)and additional 2.5 mL of THF at 45 °C for 1 h.The yields were isolated yields.The green background highlights the optimal conditions.Scheme 2. Proposed mechanism of 2a formation.

Substrates' Expansion under Optimized Conditions
Thus, the extension of the above optimized methodology as a one-pot/two-step synthesis of 3-substituted-1H-dibenzo[e,g]indazoles 2b-p starting from 2′-alkynyl-biaryl-2-aldehydes 1b-p via an intramolecular 1,3-dipolar cycloaddition is depicted in Chart 1.The corresponding p-Ts-hydrazones of 1b-p, as crucial transformations, exhibited their quantitative feasibility by being modulated with the influence of alkyne-substituents R 1 and Ar-substituents R 2 and R 3 .

Substrates' Expansion under Optimized Conditions
Thus, the extension of the above optimized methodology as a one-pot/two-step synthesis of 3-substituted-1H-dibenzo[e,g]indazoles 2b-p starting from 2 ′ -alkynyl-biaryl-2-aldehydes 1b-p via an intramolecular 1,3-dipolar cycloaddition is depicted in Chart 1.The corresponding p-Ts-hydrazones of 1b-p, as crucial transformations, exhibited their quantitative feasibility by being modulated with the influence of alkyne-substituents R 1 and Ar-substituents R 2 and R 3 .
In addition, the introduction of methyl (1f), chloro (1g), and trifluoromethyl (1h) groups at the position of R 2 showed a similar reactivity to 1a in producing 2f-h in 83-86% yields.In the case of the substrate having chloro and silyl groups (1m), the corresponding product 2m could be also obtained in an 82% yield.More interestingly, three pyridylfused analogues of 2a, 2n-p were also successfully synthesized in 88%, 90%, and 75% yields, respectively.

Proposed Mechanism
Chart 1. Extension of the optimized methodology as one-pot/two-step synthesis of 3-substituted-1Hdibenzo[e,g]indazoles 2b-p a .a Reaction conditions: 1 (1.0 mmol), TsNHNH 2 (1.1 equiv.) in 5.0 mL of THF at 45 • C for 1 h, then LiO t Bu (1.5 equiv.)and additional 2.5 mL of THF at 45 • C for 1 h.In each case, the yield refers to the effective amount of isolated compound.
In addition, the introduction of methyl (1f), chloro (1g), and trifluoromethyl (1h) groups at the position of R 2 showed a similar reactivity to 1a in producing 2f-h in 83-86% yields.In the case of the substrate having chloro and silyl groups (1m), the corresponding product 2m could be also obtained in an 82% yield.More interestingly, three pyridyl-fused analogues of 2a, 2n-p were also successfully synthesized in 88%, 90%, and 75% yields, respectively.

Proposed Mechanism
The proposed mechanism of 3-phenyl-1H-dibenzo[e,g]indazole (2a) formation is depicted in Scheme 2. In the presence of t BuO − , diazo zwitterion A forms from hydrazone 1a ′ ; then, an intramolecular nucleophilic cycloaddition occurs in the 1,3-dipole C to afford D, which, then, allows aromatization to take place to give the final product 2a.

Structural Analysis 2.3.1. X-ray Data of Compound 2a
A suitable single crystal of compound 2a was obtained through a slow evaporation from its petroleum ether/dichloromethane (5:1 v/v) solution [36].The X-ray crystal data (Figure 1

DFT Calculation of Dimeric Species of 2a and Its Tautomer
In a DMSO-d6 solvent, two types of proton peaks assigned to the N-H bond were observed in the 1 H NMR spectra of 2a, 2d, 2f, 2h, 2i, 2j, 2l, 2n, 2o, and 2p.On the basis of a DFT calculation, it is favorable to form the dimeric species with a definitely lower energy than that of the sum of the two isolated monomers resulted from the hydrogen bond in the solution; thus, there are expected to be three types of dimers, as shown in Chart 2, including a 2a dimer-anti, a 2a/2a tautomer dimer-syn, and a tautomer dimer-anti, taking two phenyl groups as reference, centered on a six-membered H-bonding chelate.We selected 2a as the representative sample for calculating the binding energies of these three dimers with DFT using the Gaussian 09 program at a B3LYP-D3(BJ)/ma-TZVP [ [37][38][39] level.An SMD solvation model was employed with the default settings.The basis set su-

DFT Calculation of Dimeric Species of 2a and Its Tautomer
In a DMSO-d 6 solvent, two types of proton peaks assigned to the N-H bond were observed in the 1 H NMR spectra of 2a, 2d, 2f, 2h, 2i, 2j, 2l, 2n, 2o, and 2p.On the basis of a DFT calculation, it is favorable to form the dimeric species with a definitely lower energy than that of the sum of the two isolated monomers resulted from the hydrogen bond in the solution; thus, there are expected to be three types of dimers, as shown in Chart 2, including a 2a dimer-anti, a 2a/2a tautomer dimer-syn, and a tautomer dimer-anti, taking two phenyl groups as reference, centered on a six-membered H-bonding chelate.We selected 2a as the representative sample for calculating the binding energies of these three dimers with DFT using the Gaussian 09 program at a B3LYP-D3(BJ)/ma-TZVP [ [37][38][39] level.An SMD solvation model was employed with the default settings.The basis set superposition error (BSSE) was corrected using the counterpoise (CP) method of Boys and Bernardi [40].The calculation results disclose that the binding energies for the formation of the 2a dimer-anti, 2a/2a tautomer dimer-syn, and tautomer dimer-anti are −8.29 kcal/mol, −8.50 kcal/mol, and −8.79 kcal/mol, respectively (Figure 2).Considering the slight differences of binding energies among these three types of dimers, the observed two types of N-H signals in the 1 H NMR spectra in DMSO-d

Materials
All commercially available reagents, solvents, and metal salts are analytically pure and were used without further purification.

Materials
All commercially available reagents, solvents, and metal salts are analytically pure and were used without further purification.cuprous iodide (CAS 7681-65-4) and lithium t-butoxide (CAS 1907-  were purchased from Macklin (Shanghai, China); the H 2 O used was ultrapure water.

General Methods
Column chromatography was performed on silica gel (300-400 mesh).Thin-layer chromatography (TLC) was performed on 0.2 mm silica gel-coated glass sheets.The NMR spectra were recorded on a JEOL ECS-400 instrument operating at 400 and 100 MHz for the 1 H and 13 C nuclei, respectively.All chemical shifts (δ H , δ C , δ F ) are given in parts per million (ppm); all homocoupling patterns ( n J H,H ) are given in hertz (Hz).No TMS was added; the chemical shifts were measured against the solvent peak taken as a reference signal; CDCl 3 , δ H = 7.26 ppm, and δ C = 77.16ppm;  , δ H = 2.50 ppm, and δ C = 39.52 ppm.The high-resolution mass spectroscopy (HRMS) spectra were obtained using high-resolution mass spectrometers with an electrospray ionization (ESI) source.The single-crystal X-ray diffraction data were obtained using a SuperNova (Agilent Technologies, Oxfordshire, UK) diffractometer with a Cu K α radiation at a low temperature (173.15K).All the NMR charts for the prepared starting materials and the products are reported in the Supplementary Materials.

General Procedure for the Preparation of 2 ′ -Alkynyl-biaryl-2-aldehydes 1a-p
(1) A THF (5.0 mL) and Et 3 N (5.0 mL) solution containing 1-bromo-2-iodobenzenes (2.0 mmol), CuI (5.0 mol%, 19.0 mg, 0.1 mmol), and PdCl 2 (PPh 3 ) 2 (5.0 mol%, 70.2 mg, 0.1 mmol) in a 25 mL screw-capped thick-walled Pyrex tube with stirring under N 2 was dropwise added to terminal alkynes (2.4 mmol) at room temperature over 5 min.The obtained mixture was then stirred at room temperature under N 2 for 12 h.After the reaction was completed (TLC monitoring, eluent pure petroleum ether), the reaction mixture was filtrated through a short pad of celite.The solution was then concentrated under reduced pressure to remove the volatiles, and the crude residue was purified using column chromatography on silica gel (eluent pure petroleum ether) to obtain the desired compounds S a -S p (checked with GC-MS) in 75-95% yields.
) indicate that the existence of intermolecular NH-N hydrogen bonds promotes the formation of a 2a dimer.The length of the NH-N hydrogen bond in the 2a dimer is 2.103 Å, and the N-N distance of the NH-N hydrogen bond is 2.845 Å. Molecules 2023, 28, x FOR PEER REVIEW 6 of 16 the formation of a 2a dimer.The length of the NH-N hydrogen bond in the 2a dimer is 2.103 Å, and the N-N distance of the NH-N hydrogen bond is 2.845 Å.

Figure 1 .
Figure 1.X-ray crystal structure of compound 2a.Carbon atoms are shown in gray, nitrogen atoms in purple, and N-H hydrogen atoms in white.The hydrogen atoms on the benzene rings are omitted for clarity.(a) View face-on to the aromatic rings showing the hydrogen bonds in the 2a dimer.Annotated with the NH-N hydrogen bonds' length and N-N distance.(b) View of a unit cell.The blue lines show the NH-N hydrogen bonds in the 2a dimer.The red lines show the NH-N hydrogen bonds between 2a and another omitted molecule.

Figure 1 .
Figure 1.X-ray crystal structure of compound 2a.Carbon atoms are shown in gray, nitrogen atoms in purple, and N-H hydrogen atoms in white.The hydrogen atoms on the benzene rings are omitted for clarity.(a) View face-on to the aromatic rings showing the hydrogen bonds in the 2a dimer.Annotated with the NH-N hydrogen bonds' length and N-N distance.(b) View of a unit cell.The blue lines show the NH-N hydrogen bonds in the 2a dimer.The red lines show the NH-N hydrogen bonds between 2a and another omitted molecule.

Chart 2 .
-1H-dibenzo[e,g]indazole 3-phenyl-2H-dibenzo[e,g]indazole 2a Structures of the expected three types of dimeric species in solution.The blue dashed lines show the NH-N hydrogen bonds.2.3.3.Temperature Gradient Experiment of compound 2a in DMSO-d6A temperature gradient experiment of compound 2a in DMSO-d6 was performed from 25 °C to 125 °C; the corresponding 1 H NMR spectra are recorded in Figure3.With the temperature increasing, it is shown that two 1 H sharp signals gradually coalesced into a unique, broad signal at 14.03 ppm at 125 °C, which results from the fast chemical exchange of 2a and 2a tautomer at relatively higher temperature.

Figure 2 .Chart 2 .Chart 2 .
Figure 2. The calculation results of the binding energies of three types of dimeric species of 2a in DMSO-d6.The calculations were performed using the Gaussian 09 program at a B3LYP-D3(BJ)/ma-TZVP level.The blue dashed lines show the NH-N hydrogen bonds.The red circles show N-H hydrogen atoms and peak of 2a, when green circles show that of 2a tautomer.

Figure 2 .
Figure 2. The calculation results of the binding energies of two types of dimeric species of 2a in DMSO-d6.The calculations were performed using the Gaussian 09 program at a B3LYP-D3(BJ)/ma-TZVP level.The blue dashed lines show the NH-N hydrogen bonds.The red circles show N-H hydrogen atoms and peak of 2a, when green circles show that of 2a tautomer.

Figure 2 . 3 . 16 Figure 3 . 1 H
Figure 2. The calculation results of the binding energies of two types of dimeric species of 2a in DMSO-d 6 .The calculations were performed using the Gaussian 09 program at a B3LYP-D3(BJ)/ma-TZVP level.The blue dashed lines show the NH-N hydrogen bonds.The red circles show N-H hydrogen atoms and peak of 2a, when green circles show that of 2a tautomer.

Figure 3 .
Figure 3. 1 H NMR spectra of compound 2a recorded in DMSO-d 6 with increasing temperature from 25 • C to 125 • C. The red circles show N-H hydrogen atoms and peak of 2a, when green circles show that of 2a tautomer.

Table 1 .
Optimization of the model's reaction conditions in the case of compound 2a.

Table 1 .
Optimization of the model's reaction conditions in the case of compound 2a.

Table 2 .
Optimal alkali bases used in the synthesis of compound 2a.