Synthesis of Azacarbolines via PhIO2-Promoted Intramolecular Oxidative Cyclization of α-Indolylhydrazones

An unprecedented synthesis of polysubstituted indole-fused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO2) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere.


■ INTRODUCTION
Selective carbon−nitrogen (C−N) bond formation is one of the most important processes in organic chemistry since it enables key steps in the synthesis of complex nitrogencontaining compounds from simple precursors. 1 Traditionally, methods for C−N bond construction were routinely focused on copper-catalyzed Ullmann−Goldberg, 2 Chan−Lam, 3 and Pd-catalyzed Buchwald−Hartwig 4 aminations using (pseudo)halocarbon or organometallic reagents. The recent maturation of methodologies (photochemical included) operating via transition-metal [Pd, Rh, Ru, Cu, etc.] catalyzed direct C−H bond amination 5 without prefunctionalization of simple starting materials offers a valuable alternative. However, these reactions generally suffer from high reaction temperature, narrow substrate scope, and high loading of the catalyst and/or metal oxidant. In addition, the contamination of heavy metals in the final product has limited their potential application in drug synthesis in the later stages. Hence, the development of alternative, effective, and safe metal-free methods for the formation of C−N bonds that can be performed at milder conditions starting from nonprefunctionalized simple precursor bonds is highly desirable. In this context, hypervalent iodine reagents 6 (HIRs) have captured our attention because of their inherent low toxicity, ready accessibility, low cost, high chemoselectivity, and mild conditions. Despite substantial advances in the oxidative C−H amination/amidation aiming at a greener goal, 7,8 to the best of our knowledge, the application of HIRs in the C(sp 2 )−H/N−H dehydrogenative coupling annulation reactions of hydrazone systems 9 to assemble Nheterocycles, especially those fused, still remains limited. Specifically, Tanimori's 9a and Zhu's 9b groups independently reported the synthesis of structurally diversified pyrazole/1Hindazole derivatives through metal-free oxidative C(sp 2 )−H cycloamination of both vinyl and aryl hydrazones (Figure 1a). Almost simultaneously, Chen, Xiao, and coauthors 9c disclosed a PhI(OAc) 2 -promoted radical cyclization of allyl hydrazones for the assembly of a wide range of five-membered dihydropyrazoles (Figure 1b). Although an excellent example describing a copper-catalyzed intramolecular C−N bond formation to afford cinnolines has been reported by Xiao, Xu, and co-workers, 10 a metal-free approach to access a fused  six-membered pyridazine skeleton from hydrazone substrates is yet to be realized.
Following our interest in the construction of polycyclic Nheterocycles 11 and aware of the privileged role of the indole nucleus in natural products and medicinal science, 12,13 we envisaged that the NH moiety in α-(indol-3-yl)hydrazones can be used as a N donor in coupling with the indole C2−H 7a,i, 14 bond in the presence of the hypervalent iodine reagents (HIRs) to construct fused indole pyridazines (Figure 1c).
Herein, we report an unprecedented example of PhIO 2promoted dehydrogenative cyclization of α-indolylhydrazones 1, whereby a sequential C−N bond formation, aromatization, N−C bond cleavage of a carbamate residue, ring expansion, and oxidative process are involved. Notably, this approach has resulted in a convenient assemblage of two biologically important heterocycles such as indole and pyridazine frame-works. The fusion of these two privileged heterocycles in one molecule 15 may create rigid entities endowed with either enhanced (synergistic effect) or new biological activities, which may feature promising bioactivity for screening. Furthermore, compared with Xiao and Xu's protocol, 10 this method offers the clear advantage of not requiring the use of transition metal catalysts and harsh reaction conditions.

■ RESULTS AND DISCUSSION
Generation of the required substrates 1 is readily achieved in 23−95% yields by ZnCl 2 -catalyzed reaction of the indoles with azoalkenes in CH 2 Cl 2 16 (see Supporting Information). The intramolecular cyclization of α-indolylhydrazone 1a was initially investigated by applying Reddy's conditions. 7e To our satisfaction, the combination of PIDA with TFA (30 mol %) in CH 2 Cl 2 at room temperature for 0.5 h afforded the  of I 2 or Cu(OTf) 2 as a promoter, led to poorer results (entries 4 and 5). It was also found that basic additives such as DBU and K 2 CO 3 had a detrimental effect, as lower yields were achieved (entries 6 and 7). Whereas Cu(OTf) 2 was crucial as an additive in previously reported iodine(III)-promoted oxidative C(sp 2 )−H cycloamination, 18 here it showed lower efficiency (entry 8). Though a more rapid consumption of αindolylhydrazone 1a was observed with the use of a stoichiometric amount of TFA, the reaction only furnished 41% yield of the desired product 2a (entry 9). Solvents like CHCl 3 , CH 3 OH, CH 3 CN, and THF (entries 10−13) were substantially less efficient in terms of the product yield. While replacing PIDA with PIFA, HTIB (Koser's reagent), or PhIO failed to furnish better results (entries 14−16), at the switching of PIDA to other hypervalent iodine(V) oxidants 19 such as IBX, DMP, and iodylbenzene (PhIO 2 ), we were pleased to witness higher yields of 1a into 2a (entries 17 −19). In particular, when PhIO 2 as an uncommon iodine(V) reagent (λ 5 -iodane) was applied, the yield was improved to 82% (entry 19). A brief re-examination of the solvents still identified CH 2 Cl 2 as optimal (entries 19 −24). No improvement in yield was attained when the reaction was performed at 50°C in DCE (entry 20) or when reducing the amount of PhIO 2 to 1.5 equiv (entry 25).
Control experiments also revealed that no product formation 2a was detected in the absence of PhIO 2 (entry 26) or TFA (entry 27). This indicated that both PhIO 2 and TFA were essential for the reaction to proceed smoothly. Therefore, the optimal reaction conditions can be summarized as follows: 0.2 mmol of substrate in CH 2 Cl 2 (2 mL) with PhIO 2 oxidant (2.3 equiv) and TFA additive (30 mol %) at room temperature for 5 h (Table 1).
With the optimal conditions in hand, the substrate scope and the limitations of the oxidative intramolecular C−H amination with PhIO 2 were investigated (Table 2). An array of α-indolylhydrazones 1a−y were explored, resulting in the expected azacarbolines 2a−y in good to excellent yields. As shown in Table 2, various substituents on the azacarboline skeleton were accommodated. Although the ester (R 3 = CO 2 Me, CO 2 Et, CO 2 i-Pr, CO 2 t-But, and CO 2 Allyl) or phosphonate (R 3 = PO(OMe) 2 ) groups in substrates 1 were well supported, the tolerance of amide (R 3 = CON(Me) 2 ) as well as the phenyl (R 3 = Ph) group was lower. It was pleasing to find that incorporation of a bisindole moiety into the substrate proved a success, furnishing intriguing polyazaheterocyclic architecture 2j. The reaction conditions were also suitable for substrates bearing R 4 alkyl groups, such as methyl, ethyl, and an n-propyl or ethyl acetate appendage. Various functional groups at the 4-, 5-, 6-, or 7-positions of the indole ring, regardless of electron-donating (Me, MeO, BnO) (2q− 2s) and electron-withdrawing (Cl, Br, F, CO 2 Me) ones (2t− 2x), were compatible with the optimized conditions. Furthermore, indole substrates with N-methyl, N-propyl, and N-benzyl (R 1 = Me, n-Pr, Bn) substituents gave good yields of cyclized products. In contrast, the NH-free indole 1p proceeded with poor conversion (21% yield), probably due to its attenuate intrinsic reactivity. Pleasantly, azacarboline 2y incorporating a ring system between the N and C7 atoms of the indole ring was also prepared in good yield. It is important to note that this transformation allowed the installation of plural functionalities that are potentially well suited for future synthetic manipulations (for example, metal-catalyzed crosscoupling reactions, etc.). Interestingly, azacarboline with phosphorus substitution (2h) could serve as novel pharmaceuticals and agrochemicals. 20 The cycloamination reaction of 1a was also conducted on a 3 mmol scale, thus demonstrating the scalability of the present method (79% yield).
To gain insight into the reaction mechanism, we carried out further control experiments (Scheme 1).
First, the application of N-tert-butyl-α-phenylnitrone (PBN) 21 or (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEM-PO) 9a as a radical scavenger evidenced that the transformation of 1a to 2a was not suppressed (51% and 48% yield, respectively, Scheme 1a). This fact suggests that radical intermediates were not involved in this process. Second, the treatment of isolated five-membered cross-coupled product C (entries 22, 25, and 27, Table 1) under the reaction conditions was found to give product 2a (Scheme 1b), the result of which indicated its effective involvement in the reaction mechanism. The preliminary formation of a less polar spot which gradually disappeared in favor of the final product 2a (TLC monitoring) also confirmed that C was the productive intermediate for this transformation. On the other hand, the same intermediate C did not work when subjected with PhIO 2 alone (Scheme 1c). Third, when the prepared hydrolyzed pyrrolo[2,3-b]indole D1 was subjected under standard conditions, the expected 2b was successfully obtained (Scheme 1d). Lastly, substrate 1z with an Scheme 1. Control Experiments a a PBN = N-tert-butyl-α-phenylnitrone; TEMPO = (2,2,6,6-tetramethylpiperidin-1-yl)oxyl). amide N-protective group (CONH 2 ) also furnished the corresponding azacarboline 2b in good yields (Scheme 1e).
Based on these results and in agreement with the previous references, a tentative mechanism for the oxidative C−H amination of α-indolylhydrazones is presented in Scheme 2.
Initially, PhIO 2 reacts with 1a to give an N-iodo intermediate A after a CH/NH tautomerization (1,3-H shift). The subsequent electrophilic cyclization (oxidative C− N bond formation) step takes place between C-2 of the indole and nitrogen activated by the electrophilic iodine species generating intermediate B with simultaneous loss of PhIO and HO − . This was then followed by the formation of key pyrrolo[2,3-b]indole intermediate C through successive deprotonation and aromatization. Finally, the hydrolysis of a carbamic residue (intermediate D), ring expansion reaction, 22 and oxidative aromatization from E afford the desired azacarboline 2a. The explanation for the role of TFA is not immediately intuited, but its beneficial effect is clearly demonstrated in these latter steps (see Scheme 1b, 1c, and 1d). 22 However, considering that the transformation of intermediate C into 2a under standard conditions is not straightforward (32% yield, Scheme 1b), an alternative reaction pathway resulting from six-membered electrophilic cyclization may also be operative. In this case, the oxidative C−N bond formation would occur at the other nitrogen atom of the hydrazone residue, which could afford the final product 2a after undergoing the hydrolysis and oxidative aromatization steps. 23 To further demonstrate the potential and synthetic usefulness of this method, the generated azacarbolines were transformed as shown in Scheme 3. The ester group at the 4position of 2a could be easily hydrolyzed by treatment with KOH in methanol at reflux. 24 Decarboxylation was possible from 3 by heating at 140°C in the presence of NaCl in DMSO/H 2 O. 25

■ CONCLUSION
In conclusion, we have developed a practical, environmentally friendly, and metal-free methodology for intramolecular oxidative cyclization of α-indolylhydrazones at room temperature. Complementary with existing methods, this approach allows direct access to scarcely represented azacarbolines 14 via dehydrogenative C(sp 2 )−N bond formation using the less emblazoned PhIO 2 26,27 hypervalent iodine(V) reagent. We believe that obtaining of such fused N-heterocyclic scaffolds that incorporate both the privileged indole and pyridazine core with the aid of a "forgotten" PhIO 2 through the not easy oxidative C−H/N−H cross coupling could open the way for further interesting novel applications.

■ EXPERIMENTAL SECTION
General Experimental Details. All the commercially available reagents and solvents were used without further purification. The following compounds were synthesized according to literature procedures: HTIB, 28 PhIO, 29 PhIO 2 , 30 IBX, 31 and DMP. 32 CAUTION! PhIO, PhIO 2 , and IBX are explosive under impact or heating to >200°C, and appropriate precautions should be taken while handling these products. However, we have not experienced any explosions while working with these compounds at room temperature.
α-(Indol-3-yl)hydrazones 1a−i,k−z were prepared according to our previously reported methods 16a,b with a slight modification. Bis(indolyl)methane hydrazone 1j was prepared following literature procedure. 16c Chromatographic purification of compounds was carried out on silica gel (60−200 μm). TLC analysis was performed on preloaded (0.25 mm) glass-supported silica gel plates (Kieselgel 60); compounds were visualized by exposure to UV light and by dipping the plates in 1% Ce(SO 4 )·4H 2 O and 2.5% (NH 4 ) 6 Mo 7 O 24 · 4H 2 O in 10% sulfuric acid followed by heating on a hot plate. All 1 H NMR and 13 C NMR spectra were recorded at 400 and 100 MHz using DMSO-d 6 or CDCl 3 as solvent on a Bruker Ultrashield 400 spectrometer (Bruker, Billerica, MA, USA). Chemical shifts (δ scale) are reported in parts per million (ppm) relative to the central peak of the solvent and are sorted in descending order within each group. The following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets, t = triplet, q = quartet, sex = sextet, sept = septet, m = multiplet, and br = broad signal. All coupling constants (J value) are given in Hertz [Hz]. High-resolution mass spectroscopy was performed on a Micromass Q-TOF Micro mass spectrometer (Micromass, Manchester, UK) using an ESI source. Melting points were determined in open capillary tubes and are uncorrected.
Procedure for the Preparation of Bis(indolyl)Methane Hydrazone 1j. 16c 1-Methylindole (0.75 mL, 6 mmol, 4 equiv) was added to a previously stirred solution of Na 2 CO 3 (1.59 g, 15 mmol, 10 equiv) in water (5 mL). The dichloroacetone hydrazone (298.5 mg, 1.5 mmol) in dichloromethane (5 mL) was added, and the reaction mixture was stirred at room temperature. Upon completion of the reaction (1 h, TLC check), the mixture was diluted with water (10 mL) and extracted with dichloromethane (3 × 20 mL), and the collected organic phases were dried over anhydrous Na 2 SO 4 . After filtration, the reaction was concentrated in vacuo, and the obtained crude was purified by flash chromatography to afford the bis(indolyl)methane hydrazone 1j.
The NMR spectra in DMSO-d 6 showed that compounds 1 exist predominantly in the hydrazone structure; however, signals related to the hydrazine tautomeric form can be also observed.