Base-Catalyzed, Solvent-Free Synthesis of Rigid V-Shaped Epoxydibenzo[b,f][1,5]diazocines

A novel method for the synthesis of epoxydibenzo[b,f][1,5]diazocines exhibiting a V-shaped molecular architecture is reported. The unique approach is based on unprecedented base-catalyzed, solvent-free autocondensation and cross-condensation of fluorinated o-aminophenones. The structure of the newly synthesized diazocines was confirmed independently by X-ray analysis and chiroptical methods. The rigidity of the diazocine scaffold allowed for the separation of the racemate into single enantiomers that proved to be thermally stable up to 140 °C. Furthermore, the inertness of the diazocine scaffold was demonstrated by performing a series of typical transformations, including transition metal-catalyzed reactions, proceeding without affecting the bis-hemiaminal subunit.


■ INTRODUCTION
Molecules possessing rigid structures with defined curvature constitute the underpinnings of the rapidly growing supramolecular chemistry area. Those small building blocks decorated with appropriate functional groups enable the formation of higher-order structures as a result of selfassembly, which is of use in many areas. The most impressive examples include molecular tweezers, 1 capsules, 2 or cages. 3 Among the molecular building blocks mentioned above, marked interest has been focused on Troger's base, a small molecule with a great history (structure A in Scheme 1). Its unique rigid V-shaped structure, confirmed almost 50 years after its first synthesis, 4 has spawned an enormous number of applications in many areas, such as molecular recognition, 5 metal catalysis, and organometallic 6 and medicinal chemistry. 7 The basis for widespread application arises from its trivial synthesis, carried out directly from aniline (or its derivatives) and paraformaldehyde (Scheme 1). This clearly underlines that each new, easily accessible building block for the construction of the supramolecular architecture stimulates an enormous development of the field. For these reasons, sustainable, practical methods for the synthesis of bent molecular bricks are still highly desirable.
The long-standing interest in Troger's base (A) has recently culminated in the efficient synthesis of its heteroatom analogues, epiminodibenzodiazocines, bearing a nitrogen bridge (structure B in Scheme 1). 8 In contrast, to the best of our knowledge, no efficient synthetic approach to diazocines, bearing an oxygen bridge, has been developed so far (structure C in Scheme 1). We anticipated that the missing link should be easily provided by the autocondensation of o-aminophenones, providing a new scaffold for supramolecular chemistry. A careful inspection of the literature data revealed that epoxydibenzo [b,f ][1, 5]diazocines have been isolated as byproducts in the synthesis of heterocycles 9 and natural product degradation studies in some cases, albeit in marginal yields. 10 Herein, we wish to report an unprecedented solvent-free synthesis of epoxydibenzo [b,f ] [1,5]diazocines with a welldefined, rigid V-shaped structure from fluorinated o-aminophenones.

■ RESULTS AND DISCUSSION
Our working hypothesis was based on the assumption that fluorinated o-aminophenones could undergo base-catalyzed self-condensation (Table 1). To prove this, we initially screened more than 10 solvents of different polarity in the autocondensation reaction of 1a, catalyzed by N,N,N′,N′tetramethylguanidine (TMG) (for details, see Scheme S1). The respective diazocine 2a was formed in all cases in good to excellent yield without the concomitant formation of byproducts such as imine or cyclic bisimine (Table 1). Astonishingly, the best results in terms of conversion and yield were achieved under solvent-free conditions, leading to diazocine 2a in 93% yield on a 0.5 mmol scale and finally in 95% yield on a 4.5 mmol scale. It should be mentioned that nitrogen-protected aminophenones 1b−d, including an acidic sulfonamide (1d), failed to react, whereas o-aminobenzaldehyde decomposed completely under solvent-free conditions (for details, see the Supporting Information).
With the optimal conditions secured, the scope of the method was explored. First, a group of trifluoromethyl aminophenones bearing electron-withdrawing and electrondonating groups in the para position to the nitrogen were investigated (Scheme 2). Generally, the formation of epoxydibenzo [b,f ] [1,5]diazocines proceeded in high yields, and the presence of halogen atoms (including fluorine) 2c, alkyl ester 2h, dimethylamine 2g, or methoxy function 2f was admirably tolerated. Only incorporation of the trifluoromethyl group that exerts a strong positive σ-inductive effect has delivered diazocine 2i in a low 23% yield. A further increase in the reaction time to 48 h slightly increased the yield to 39% (for details, see the Experimental Section). Uniformly, diazocine 2j carrying a perfluorinated side chain was also isolated in a moderate 41% yield. In contrast, the presence of a methyl group and alkoxy side chains bearing alkene or alkyne moieties afforded smoothly diazocines 2k−n. Notably, the autocondensation of alkene-or alkyne-derived aminophenones had to be performed at a lower temperature (80°C) to maintain the high yield. The application of enantiomerically pure aminophenones has met with partial success, leading cleanly to diazocine 2q. However, an almost equimolar mixture of diastereomers was detected by 19 F NMR. Further studies revealed that less nucleophilic aminopyridine derivatives could also participate in the autocondensation to give diazocines 4a− c.
Next, we examined whether a more challenging, slightly acidic difluoromethyl ketone, 11 prone to undergoing enolization and subsequent aldol reaction, could be involved in the TMG-catalyzed autocondensation (TMG; pK a ≈ 15.2 in  12 The incorporation of the CF 2 H group into organic molecules has received a great deal of attention in medicinal chemistry 13 due to its ability to act as a lipophilic hydrogen bond donor modifying permeability, binding affinity, and bioavailability. 14 The engagement in weak interactions offers an ideal platform for the construction of higher-order molecular scaffolds. 15 To our delight, diazocine 2o was formed in 70% yield under basic conditions without competing side reactions. The unique, rigid V-shaped structure was further evidenced by X-ray analysis (Scheme 2, structure 2o) showing a perpendicular arrangement of the two aromatic rings, similar to Troger's base. 16 The requirements for new building blocks in supramolecular chemistry include ready access to useful quantities of the compounds. Indeed, the autocondensation proved to be scalable, and there was no need for special equipment. Simply heating 1 g of aminophenones (∼5.0 mmol) in a 4 mL closed vial in the presence of a drop of TMG (20 mol %) cleanly furnished the respective products 2b, 2c, 2e, 2h, 2k, 2l, and 2n without any erosion in yield in comparison to a 0.5 mmol scale. The challenging CF 2 H-substituted compound also afforded derivative 2o in a high 70% yield, emphasizing the practical aspect of the developed method.
With excellent results in the autocondensation process, further investigations were directed to cross-condensation. A careful choice of aminophenones prompted by the different rates of autocondensation and a disparate polarity under chromatographic conditions enabled the isolation of a series of diazocines 5a−e. The key for successful cross-condensation was mixing aminopyridine 3 with a 2-fold molar excess of aminophenone 1. 17 A chiral aminophenone bearing a pmenthyloxy group also afforded diazocine 5e in 56% yield, though as a mixture of diastereomers in a ratio close to 1:1 (Scheme 3). Unfortunately, the sterically encumbered methyl substituent located in the ortho position adjacent to the reactive amino group suppressed cross-condensation (Scheme 3, structure 5f).
The synthetic potential of the diazocine products was demonstrated by a series of well-established transformations proceeding without affecting the diazocine core (Scheme 4). First, we turned our attention to the pyridinium salt structural motif, which proved to be useful in many areas 18 such as molecular recognition, 19 catalysis, 20 and medicinal chemistry. 21 Gratifyingly, the treatment of diazocines 5a and 4b with MeI cleanly afforded salts 6a and 6b, respectively, without competitive opening of the oxygen bridge under the action of the strong alkylating agent. Moreover, the bisester function was used to surround the hydrophobic cavity of the V-shaped structure by hydrogen bond donors, useful in molecular recognition. The respective bisester 2h was easily converted into bisamide 8 using achiral or chiral amino alcohols through a TBD-catalyzed protocol. Finally, carbon−carbon multiple bonds could also play a role in further functionalization without affecting the diazocine scaffold in metal-catalyzed reactions. Thus, bisalkene 2l underwent a cross-metathesis reaction (CM) with acrylate, whereas bisalkyne 2k provided bis-1,2,3-triazole 10 in high yield under standard conditions.
With regard to future applications, the most appealing feature of these systems is their stability in the enantiomerically pure form. Indeed, our initial experiments enabled the separation of racemic 2a into single enantiomers on a preparative scale (Scheme 5). To assign the absolute configuration of the two enantiomers of 2a, electronic and vibrational circular dichroism (ECD and VCD, respectively) spectra were recorded in acetonitrile and then simulated using quantum chemical methods (DFT and TDDFT). These two chiroptical spectroscopies are very sensitive to any stereo-  chemical changes of the chiral system because they rely on electronic and vibrational transitions spanning the entire UV− vis−mid-IR spectral range. Thus, their complementary combinations provide a holistic view of the properties of any chiral molecules, enabling the conclusive assignment of their absolute configuration in solution and also deeper insight into dynamic stereochemistry. 22 The ECD and VCD spectra of (+)-2a and (−)-2a display a perfect mirror-image relationship, confirming the enantiomeric relationship of these two newly synthesized diazocines separated by HPLC, as well as their high optical purity (Scheme 5, part A). The determination of the absolute configuration was based on the comparison of experimental and computed ECD and VCD spectra for an arbitrarily chosen R,R-enantiomer of 2a. A conformational search using the MMFF94s force field within 10 kcal/mol followed by DFT geometry optimizations at the ωB97X-D/6-311+G(d,p)/ PCM/CH 3 CN level of theory revealed only one stable conformation, indicating ipso facto the extremely high rigidity of the diazocine core. Moreover, the high configurational and conformational stability was also proved experimentally using variable-temperature ECD measurements by heating the decalin solutions of 2a to 180°C ( Figure S2). The very close similarity between experimental and calculated ECD and VCD spectra observed in Scheme 5 (parts B and C) led to the conclusion that the absolute configuration of (+)-2a is R,R, with S,S for (−)-2a ( Figure S2). It should be noted that the similar Troger's base and its derivatives underwent racemization, especially in the presence of Brønsted of Lewis acids, which makes diazocine 2a the superior platform for further derivatization.

■ CONCLUSIONS
In conclusion, we have established a new base-catalyzed, solvent-free condensation of fluorinated o-aminophenones for the construction of epoxydibenzo [b,f ][1,5]diazocines. This unprecedented approach offers easily scalable access to a broad range of diazocines bearing a unique V-shaped structure, which was confirmed by X-ray and chiroptical analysis. The rigid molecular architecture allowed the separation of racemic diazocines into single enantiomers and proved their configurational stability by ECD measurements up to 140°C. The ability to create a hydrophobic cavity by dibezo [b,f ][1,5]diazocines, closely resembling Troger's base, opens up a plethora of possible applications in the area of supramolecular chemistry, which is now an ongoing subject in our group.

■ EXPERIMENTAL SECTION
General Remarks. NMR spectra were recorded in CDCl 3 , DMSO-d 6 , or CD 3 OD solutions (unless indicated otherwise); chemical shifts are quoted on the δ scale, with the solvent signal as the internal standard (CDCl 3 , 1 H NMR δ 7.26, 13 C NMR δ 77.00; DMSO-d 6 , 1 H NMR δ 2.50, 13 C NMR δ 39.40; CD 3 OD, 1 H NMR δ 3.31, 13 C NMR δ 49.00). High-resolution mass spectra (HRMS) were recorded using an EI technique or electrospray ionization (Supporting Information). Column chromatography was performed on Merck silica gel 60 (230−400 mesh) or alumina oxide 90 active basic (0.063−0.200 mm, Merck) using a standard glass column or a CombiFlash EzPrep system. TLC was performed on aluminum sheets, Merck 60F 254, or aluminum oxide. Optical rotations were recorded on a Jasco P-2000 polarimeter. Melting points were determined on a hot-stage apparatus and are uncorrected. Anhydrous solvents were obtained by distillation over CaH 2 (DCM) or Na/benzophenone (THF, hexane, and MTBE). Air sensitive reactions were performed in flame-dried glassware under an argon atmosphere. Organic extracts were dried, and solvents were evaporated on a rotary evaporator. Reagents were used as they were purchased unless otherwise indicated. Aminophenones were synthesized starting from o-nitroaldehyde by the addition of the CF 3 anion/reduction of NO 2 / oxidation 23 sequence (1b and 1h) or orthometalation protocol (1a, 24 1c−g, 1i−k, 1o−q, 25 1h, 26 1s and 1t, 24 1u, 27 1x, 28 and 3a−c 25 ), according to the literature procedure (for the structure of oaminophenones used in this study, see Figure S1).
Synthesis of Aminophenones by the Addition/Reduction/ Oxidation Sequence. General Procedure for the Synthesis of Trifluoroethanol Derivatives via the Addition of Ruppert−Prakash Reagent to Aldehydes (GP1). To a cooled solution of aldehyde (the temperature of the cooling bath was kept in the range from −20 to −10°C; the exact temperature is given in each case) in anhydrous THF was added TMSCF 3 (1.2 equiv). Then a catalytic amount of a solution of TBAF (1 mol %) in THF (1 M) was added dropwise (Caution! In some cases, strong exothermic reaction was observed); the cooling bath was removed, and the resulting mixture was stirred for 16 h at rt (TLC analysis usually indicated the presence of silyl ether). Then a solution of TBAF (usually 0.1 mL/mmol of starting aldehyde) and water (usually 0.1 mL/mmol of starting aldehyde) were added, and the mixture was stirred until silyl ether hydrolysis occurred. The reaction mixture was evaporated and redissolved in EtOAc. The solution was washed with water (twice) and brine (twice), dried over Na 2 SO 4 , and evaporated. The residue was chromatographed on silica to give pure trifluoroethanol derivatives.
General Procedure for the Oxidation of Trifluoroethanol Derivatives to o-Aminophenones (GP2). To a three-necked roundbottom flask was added anhydrous toluene followed sequentially by CuCl (5 mol %) and 1,10-phenanthroline (5 mol %). The black complex was immediately formed, and the resulting suspension was stirred at rt for 10 min. Then diethyl hydrazinodicarboxylate (DEAD-H 2 , 495.6 mg, 1.08 mmol) was added followed by solid K 2 CO 3 (2.0 equiv), and the mixture was stirred for an additional 5 min. Then alcohol 12 (2.78 g, 11.3 mmol) was added (as a solid in one portion), and the solution was heated at 90°C (temperature of the oil bath) for 1 h. To secure the maximum conversion, O 2 was bubbled through the solution for 1 h (Caution! Special care should be taken due to low flash point of toluene, 4.4°C). Then the reaction mixture was allowed to cool to rt and filtered through a pad of Celite. The filtrate was concentrated in vacuo and chromatographed on silica to give oaminophenones (in some cases, fluorinated ketones were further purified by crystallization).
General Procedure for the Synthesis of Symmetric Epoxydibenzo [b,f ][1,5]diazocines (GP3). Fluoromethylketone 1 (x mmol) and N,N,N′,N′-tetramethylguanidine (TMG, 20 mol %) were placed in a screw-cap 4 mL vial, and the resulting mixture was heated at 120°C (IKA heating block, temperature of the reference vial filled with silicon oil). Then the reaction mixture was diluted with EtOAc or DCM (10 mL), adsorbed on silica (or aluminum oxide), and chromatographed to give the corresponding dibenzo [b,f ][1,5]diazocines 2. The analytical sample was crystallized from a given solvent to measure the melting point.
ECD spectra at variable temperatures were measured in decalin (c = 2.75 × 10 −4 M) using a Jasco J-715 spectrometer equipped with a dedicated variable-temperature transmission cell holder from Specac. The spectra of (+)-and (−)-2a were recorded from 190 to 400 nm in a quartz cell with a path length of 0.1 cm. Baseline correction was achieved by subtracting the spectrum of decalin obtained under the same conditions. All spectra were normalized to Δε (cubic decimeters per mole per centimeter) using volume correction for decalin.
VCD spectra of enantiomers (+)-and (−)-2a were recorded simultaneously with IR spectra by a ChiralIR-2X instrument from BioTools (Jupiter, FL) at a resolution of 4 cm −1 in the range of 2000−900 cm −1 using CD 3 CN as a solvent. A solution with a concentration ∼0.2 M was measured in a BaF 2 cell with a path length of 100 μm. Spectra were recorded for approximately 3 h to improve the signal-to-noise ratio. Baseline correction was achieved by subtracting the spectrum of a solvent recorded under the same conditions.
Computational Details. A conformational search was carried out at the molecular mechanics level using the MMFF94s force field within 10 kcal/mol for (+)-2a. Next, the found structure was submitted for DFT optimization using Gaussian16 [1] at the ωB97X-D/6-311+G (d,p) level of theory applying PCM for CH 3 CN.
The same level of theory was used for VCD and IR simulations. The VCD simulated spectrum was converted to Lorentzian bands with an 8 cm −1 half-width and was scaled by 0.982 (the best scaling factor, giving the best agreement between the experimental and simulated spectra).
TDDFT calculations of the final ECD spectrum were carried out using the CAM-B3LYP functionals with the def2-TZVP basis set and PCM model for CH 3 CN. The calculations at the B3LYP/def2-TZVP/ PCM and ωB97X-D/def2-TZVP/PCM levels yielded consistent results. Rotatory strengths were calculated using both length and velocity representations. The differences between the length and velocity of the calculated values of the rotatory strengths were <3%, and for this reason, only the velocity representations (R vel ) were taken into account. The UV and ECD spectra are simulated by overlapping Gaussian functions for 40 electronic transitions using bands with a 0.3 eV exponential half-width and red-shifted by 13 nm (UV correction).