Substituent-controlled construction of A4B2-hexaphyrins and A3B-porphyrins: a mechanistic evaluation

A substituent-dependent construction of novel A3B-porphyrins along with A4B2-hexaphyrins was realized by the reactions of N-tosylimines and meso-aryl-substituted tripyrranes in the presence of Cu(OTf)2 as the catalyst. The reaction mechanism of the presented method was studied on model reactions by electrospray-ionization time-of-flight (HRESI–TOF) mass spectral analysis in a timely manner. The analytical results indicated that the observed azafulvene-ended di- and tripyrrolic intermediates are responsible for the formation of porphyrinogen and hexaphyrinogen forms.

In our previous studies, we used N-tosylimines throughout the syntheses of several porphyrinic compounds which emphasized Scheme 1: Retrosynthetic method for A 4 B 2 -hexaphyrin and A 3 B-porphyrin synthesis.
the usability of N-tosylimines with dipyrromethanes, tripyrranes, or bilanes instead of aldehydes in the synthesis of porphyrins and contracted/expanded porphyrins [26][27][28].It was shown that the reaction of meso-pentafluorophenyl-substituted N-tosylimine and 5,10-bis(pentafluorophenyl)tripyrromethane formed A 6 -hexaphyrin as the main product along with the inevitable formation of side products, A 4 -porphyrin and higher expanded porphyrins [28].meso-Phenyloligopyrroles having electron-rich substituents at the 2-, 4-, or 6-positions were screened in the literature.To the best of our knowledge, hexaphyrin synthesis from the least substituted aryls appears to be not much studied.In the following study, we focused on the use of less hindered variety of precursors in hexaphyrin and porphyrin synthesis via the Cu(OTf) 2 -catalyzed reaction of tripyrrane and tosylimine according to the retrosynthetic method given in Scheme 1.Here, we present the substituent-dependent selective construction of A 4 B 2 -hexaphyrins and A 3 B-porphyrins with good yields without the formation of expanded counterparts.Beyond the synthesis, for better understanding of the product formation, mass spectral analyses of model reactions were investigated by time-dependent electrospray-ionization time-offlight (HRESI-TOF) technique.

Results and Discussion
Reactions of meso-pentafluorophenyl-substituted A 2 -tripyrrane 1 and N-tosylimines 2 were performed in the presence of Cu(OTf) 2 (Table 1).Initially, the unsubstituted phenyl-bearing N-tosylimine 2a was reacted with tripyrrane 1 in CH 2 Cl 2 under previously reported conditions [28], however, the desired hexaphyrin could not been isolated.Under these conditions, only product 3a, which is defined as A 3 B-type porphyrin was isolated with 15% yield (Table 1, entry 1).Then, we run the reactions of A 2 -tripyrrane 1 with mesityl-containing tosylimine 2b and 2,6-dichlorobenzylidene-substituted substrate 2c.The desired A 4 B 2 -hexaphyrins 4b and 4c were obtained in 17% and 16% yield, respectively (Table 1, entries 2 and 3).Next, to elucidate the role of substituents present in the aromatic part of the N-tosylimines, the monohalogenated N-tosylimines 2d-f and N-tosylimine 2g with a strongly electron-withdrawing CF 3 substituent in the 4-position were subjected to the reaction with tripyrrane 1.These para-substituted N-tosylimines provided the A 4 B 2 -hexaphyrins 4d-g (Table 1, entries 4-7), with the A 4 B 2hexaphyrin 4d isolated with 18% yield.The products 4e-g were obtained in 7-10% yield and their formation was corroborated by HRMS spectral analysis (Figures S64-S66 in Supporting Information File 1).In these reactions, the A 3 B-porphyrins concomitantly formed in yields between 9-17%.When p-methoxyand p-hydroxy-substituted N-tosylimines 2h and 2i were used in this reaction, substrate 2h gave only the A 3 B-porphyrin while the imine 2i did not form any product (Table 1, entries 8 and 9).To further evaluate the scope of the reaction, heteroaryl-bearing tosylimines were also tested.The thiophene-substituted tosylimine 2j gave hexaphyrin 4j in 17% yield and porphyrin 3j in 10% yield, whereas the indole-bearing tosylimine gave only A 3 B-porphyrins but no A 4 B 2 -hexaphyrin (Table 1, entries 10 and 11).Signals of trace amounts of A 2 B 2 -type porphyrins were detected in the mass spectra of some of the products. 1H NMR analysis of the synthesized hexaphyrins proved that the spectra were in consistence with [26]hexaphyrin aromaticity [29].Several other metal triflates such as Zn(OTf) 2 , Gd(OTf) 3 , and Yb(OTf) 3 were also tested as catalysts in the reaction of 4-fluorophenyl-substituted tosylimine 2d and tripyrrane 1 and lower yields of the A 4 B 2 -hexaphyrins and A 3 B-porphyrins were obtained compared to the reaction catalyzed by Cu(OTf) 2 (Table S2 in Supporting Information File 1).
The synthesis of A 3 B-porphyrins is effortful and only few studies have been reported involving the use of A 3 -bilanes [30,31] or dipyrromethane-dicarbinols [32], the modification of A 4 -porphyrins [33], or the reaction of pyrrole with different aldehydes [34].In the present work, the applied synthetic method provided the A 3 B-porphyrins in a single-step reaction from bispentafluorophenyl-substituted tripyrrane 1 and variously substituted N-tosylimines 2 along with the targeted a Isolated yields after flash column chromatography; b identified by HRMS analysis, NMR spectra could not be recorded due to low solubility.
[26]hexaphyrins.Additionally, each reaction was also run with aldehydes to compare the effectiveness of N-tosylimines and aldehydes on this system.In most cases, the yields were lower than those in the reactions with N-tosylimines for both A 4 B 2hexaphyrins and A 3 B-porphyrins (Table S1 in Supporting Information File 1).
Until now, we have investigated the effect of substituents present in the aryl substituent of the N-tosylimines on the product formation.At this point, we chose 5,10-bis(4-trifluoromethylphenyl)tripyrromethane (5) as a representative example to investigate the role of the tripyrrane on the reaction.A series of reactions of tripyrrane 5 with tosylimines 2c,d,f,h,l,m were performed.In this case, tripyrrane 5 principally formed A 3 Bporphyrins (Table 2, entries 1-6) and in some cases A 2 B 2 -porphyrins, but disfavored the formation of A 4 B 2 -hexaphyrins.As outlined in Table 2, the reactions of N-tosylimines 2d,f,l,m with tripyrrane 5 resulted in the formation of A 3 B-porphyrins 6b,c,e,f in yields ranging between 12-28%, respectively, where the corresponding A 2 B 2 -porphyrins were formed in trace amounts (Table 2, entries 2, 3, 5, and 6).A 3 B-porphyrin 6a was isolated as the sole product with 13% yield (Table 2, entry 1).In the case of N-tosylimine 2h, the reaction gave A 3 B-porphyrin 6d and trans-A 2 B 2 -porphyrin 7d with 21% and 10% yield, respectively (Table 2, entry 4).
In this work, the role of substituents on tripyrranes and N-tosylimines on product formation has been shown and the synthesis of A 3 B-porphyrins and a variety of A 4 B 2 -hexaphyrins has been achieved.The presence of the bulky electronwithdrawing pentafluorophenyl group in tripyrranes controls the formation of A 4 B 2 -hexaphyrins as mentioned by Osuka and Suzuki [13], besides the formation of A 3 B-porphyrins.On the other hand, electron-withdrawing but less bulky (4-trifluoromethylphenyl) groups on tripyrrane 5 led to predominant formation of the A 3 B-porphyrin even when it was reacted with mono-, di-, or penta-substituted aryl N-tosylimino substrates (Table 2).
To elucidate the product diversity and to follow the progress of the reaction, a series of mass spectral analysis of the reaction mixture of 4-fluorophenyl-substituted N-tosylimine 2d and After two minutes, tripyrrane sulfonamide II and azafulvene I mass peaks were observed.Later on, tripyrrolic intermediates III and VI predominated and the mass peak of IV was observed with poor intensity in the spectra (Figure 1 and Figure S47 in Supporting Information File 1).
In our previous works, we have shown that the reaction of pyrrole with N-tosylimines leads to pyrrole sulfonamides as the main products [35].In another work, in the synthesis of dipyrromethane structures, we have proven the formation of azafulvene intermediates by Cu(OTf) 2 -appended elimination of sulfonamide groups from pyrrolic sulfonamides [36].Here in this work, during the reaction at 0 °C, intermediates I-VI were detected (Figure 1).The primary intermediates II and IV are formed by the addition of tripyrrane 1 to tosylimine 2d.Further elimination of N-tosyl group(s) from these intermediates gives azafulvene-ended secondary intermediates III, V, and VI.The observed intermediates I-VI having sulfonamide or azafulvene ends are in accordance with our previous findings [26,35,36].In addition, the observation of azafulvene I could be attributed to the fragmentation of tripyrrane 1, intermediates II or III as pro- A similar LC-MS analysis was made for the reaction of tripyrrane 5 and 4-methoxyphenyl-substituted tosylimine 2h at 0 °C which mainly formed A 3 B-porphyrins.This time, the primary tosylated intermediates were not detected, instead N-tosyl eliminated azafulvene-ended secondary intermediates VII-XII (Figure 2) were observed, respectively, at m/z = 224.0627([M + H] + calcd for C 12 H 9 F 3 N, 224.0682), m/z = 445.1150S49 in Supporting Information File 1).Although the positive ion peaks of tripyrrolic intermediates XI and XII were observed, any hexaphyrin products did form from this set of reactions.Yet, A 3 B-porphyrins were clearly and selectively formed over A 2 B 2 -porphyrins, even the positive ion peaks of dipyrrolic intermediates VIII, IX, and X have been observed (Figure S49 in Supporting Information File 1).A reaction pathway for the predominant formation of A 3 B-porphyrin considering the reaction of tripyrrane 5 and tosylimine 2h was also proposed and is given in Figure S50 of Supporting Information File 1, in which only the azafulvene-ended intermediates VII-XII were detected.

Conclusion
In conclusion, a set of A 4 B 2 -hexaphyrins and A 3 B-porphyrins were selectively synthesized through the Cu(OTf) 2 -catalyzed reactions of N-tosylimines and tripyrranes under mild reaction conditions.With these reactions, it has been shown that the C 6 F 5 group led to the formation of hexaphyrin and porphyrins as well as the monosubstituted aryl-bearing N-tosylimines, but a 4-(CF 3 )C 6 H 4 group led only to the formation of porphyrin compounds.
A mechanistic perspective for the formation of porphyrinic products was acquired via a set of high-resolution mass analyses of selected model reactions.The results indicated that azafulvene-ended tripyrrolic intermediates III, V, and VI or sulfonamide-ended intermediates II and IV along with monopyrrolic fragment I derives the formation of porphyrins and hexaphyrins.This study offers an insight to the design of A 4 B 2hexaphyrins and A 3 B-porphyrins by utilizing the substituents on tripyrranes and N-tosylimines.
Synthesis of porphyrin compounds 3a-h,j,k and 4b-g,j N-Tosylimine 2 (0.090 mmol) and Cu(OTf) 2 (0.0090 mmol) were dissolved in CH 2 Cl 2 (0.5 mL) and stirred at room temperature for 30 minutes under N 2 atmosphere.To this mixture was added a solution of 5,10-bis(pentafluorophenyl)tripyrromethane (1, 0.090 mmol) in CH 2 Cl 2 (1.5 mL) and the mixture was stirred at rt for 4 h.Afterwards, DDQ (0.180 mmol) was added to this solution and stirred for another 2 h.The resulting solution was eluted through a short silica gel column with EtOAc and the solvent was removed under reduced pressure.

Synthesis of porphyrin compounds 6a-f and 7d
N-Tosylimine 2 (0.097 mmol) and Cu(OTf) 2 (0.0097 mmol) were dissolved in CH 2 Cl 2 (0.5 mL) and stirred at room temperature for 30 min under N 2 atmosphere.To this mixture was then added a solution of 5,10-bis(4-trifluoromethylphenyl)tripyrromethane (5, 0.097 mmol) in CH 2 Cl 2 (1.5 mL) and stirred at rt for 4 h.Afterwards, DDQ (0.195 mmol) was added to this solution and stirred for another 2 h.The resulting solution was eluted through a short silica gel column with EtOAc and the solvent was removed under reduced pressure.

Figure 1 :
Figure 1: Mass spectrum of the reaction mixture of 1 and 2d at 30 min at 0 °C with assigned intermediates (positive ion mode).

Figure 2 :
Figure 2: Intermediates in the reaction mixture of 5 and 2h at 30 min at 0 °C.

Table 2 :
Synthesis of A m B n -type porphyrins with electron-deficient tripyrrane 5.
a Isolated yields after flash column chromatography; b identified by HRMS analysis.tripyrrane 1 has been conducted at 0 °C.Samples were taken from the reaction medium at certain time intervals within 2 hours and examined by ESI LC-MS. in Supporting Information File 1).At the very first two minutes of the reaction run at 0 °C no mass signals attributable to reaction intermediates were observed but only signals of the starting materials 1 and 2d both in the negative and positive ion mode.