C.3. Result and discussions

Our two steps synthetic strategy involves the aldol addition of 2-nitrobenzaldehyde on acridinone derivatives, which upon treatment with iron/acetic acid produces the corresponding 6,7-dihydrodibenzo[b,j][1,7]phenanthroline derivatives (Scheme

II.C.3.

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Scheme

II.C.3.

Initially, we focused our attention to synthesize the starting materials. At first, acridinone derivatives (1a, 1k-1s) were prepared by the recently reported protocol developed by our group¹¹ and the substrates (3a-3z) were prepared via base mediated aldol addition in water.

When acridinone derivatives were treated with 2-nitrobenzaldehyde in water in the presence of triethylamine at 0-5^oC, the expected product (3a) was formed in good yield. When this compound was treated with iron/acetic acid at room temperature, the desired product 6,7-dihydro dibenzo[b,j][1,7]phenanthroline (4a) was formed after 6h in 38% yield. The structure of the product was confirmed by ¹H, ¹³C NMR spectroscopy, MS, HRMS, and single-crystal X-ray analysis (Figure 3).

Figure II.C.3.1: Crystal structure of compound 4a²⁸

Aiming to increase the yield of the product and also to decrease the reaction time, we tested the reaction at different temperature. At 50 ^oC, the yield of the product was increased to 73%

in 1.5h. Interestingly, at 70 ^oC, the expected product (4a) was obtained as the sole product in 86% yield after 1h. However, there was no increment in product yield as well as no decrement

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in the reaction time was observed, when the reaction was conducted at 90 ^oC and under reflux conditions (Table 1).

Table II.C.3.1:Optimization of reaction conditions

Entry^a Solvent Temp (^oC) Time (h) Yield (%)^b

1 Acetic acid r.t. 6 38

2 Acetic acid 50 1.5 73

3 Acetic acid 70 1 86

4 Acetic acid 90 1 85

5 Acetic acid Reflux 1 78

aAll the reactions were performed on 1mmol scale. ^bIsolated yields.

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TableII.C.3.2: Synthesis of various substituted 6,7-dihydro dibenzo [b,j][1,7]phenanthrolineby Fe/AcOH mediated intramolecular reductive cyclization

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aAll the reactions were performed on a 1 mmol scale. ^bYields were refers to isolated and purified compounds.

Encouraged by this interesting result, we applied the same reaction conditions to the differentsubstituted 2-(hydroxy(2-nitrophenyl)methyl)-3,4-dihydroacridin-1(2H)-ones (3a-3j), which are obtained from different substituted 2-nitrobenzaldehydes. The results are summarized in Table 2. It is interesting to note that, the reactions of substrates bearing both electron withdrawing groups (F, Cl, Br) as well as electron donating groups (CH₃, OCH₃, OBn) proceeded with equal ease and produced the desired products in good to excellent yields (Table 2, entries 1-10).

Next, we turned our attention to examine the substrate scope of this method. In this regard, various 2-(hydroxy(2-nitrophenyl)methyl)-3,4-dihydroacridin-1(2H)-ones (3k-3s) having substitution on acridinone ring was tested. At first, compounds bearing substituents on R² position of acridinone ring were examined. The substrates bearing both electron withdrawing substituents (F, Cl and Br) and electron donating substituent (CH3) gave good to excellent yields of products (Table 3, entries 1-4). Then, to our delight, we obtained excellent yields of product for the R⁴ substituted substrates (entries 5-7). In the case of disubstituted substrates also, the reaction produced good yields of products (entries 8 and 9).

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Table II.C.3.3: Substrate scope of Fe/AcOH-mediated intramolecular reductive cyclization

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aAll the reactions were performed on a 1 mmol scale. ^bYields were refers to isolated and purified compounds.

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To extend the scope of our protocol, we selected substrates bearing substituents on both acridinone and phenyl rings (3t-3y), the reaction proceeded smoothly and produced good yields of products (entries 10-15). Finally, we applied this method to a dimethyl substituted derivative, 2-(hydroxy(2-nitrophenyl)methyl)-3,3-dimethyl-3,4-dihydroacridin-1(2H)-one (3z) which was prepared from 3,3-dimethyl-3,4-dihydroacridin-1(2H)-one and 2-nitrobenzaldehyde. Under the optimized conditions, the compound 3z undergone reductive cyclization and produced the desired product (4z) in excellent yield.

SchemeII.C.3.1: Large-scale synthesis of 6,7-dihydrodibenzo [b,j][1,7]phenanthroline (4a) To illustrate the scalability of our protocol, we performed the reductive cyclization reaction in gram scale. 13.9g (40 mmol) of 2-(hydroxy(2-nitrophenyl)methyl)-3,4-dihydroacridin-1(2H)-one (3a) was treated with 11.2g of iron powder and 80 ml acetic acid at 70 ^oC. The desired product 6,7-dihydrodibenzo[b,j][1,7]phenanthroline (4a) was obtained in 81% yield. Hence, this protocol is applicable for gram scale preparations.

Moreover, based on the previously reported protocols, we tested the reaction in one-pot condition without the isolation of aldol addition/condensation products. Firstly, we performed the reaction via in-situ formation of 2-aminobenzaldehydes. The reaction failed to produce the desired product in the SnCl₂/ZnCl₂ system^10g and only a trace amount of product was formed in SnCl₂.2H₂O system.^10hIn the former case, the starting acridinone (1a) derivative was decomposed, however, in later case the starting acridinone (1a) was intact and 2-aminobenzaldehyde was decomposed due to high temperature of the reaction. Since aldol reaction can be performed in acidic conditions,¹⁸ we conducted the reaction in the presence weak and strong acids.The expected aldol addition/condensation product was not formed in both cases. The experimental results reveal that these methods are not applicable to the synthesis of 6,7-dihydrodibenzo[b,j][1,7]phenanthroline derivatives.

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Next, we sought to demonstrate the synthetic utility of the obtained polycyclic compounds (Scheme 4). The presence of bromo group at the C-2 position of 6,7-dihydrodibenzo [b,j]

[1,7]phenanthroline allows us to make further structural elaboration through conventional C-C bond formation reactions. Sonogashira¹⁹ and Suzuki²⁰ reactions are well known cross-coupling reactions for the formation of carbon-carbon bonds.

In this regard, for Sonogashira coupling, we treated 2-bromo-6,7-dihydrodibenzo[b,j][1,7]

phenanthroline (4m) with phenyl acetylene in the presence of bis(triphenylphosphine)palladium(II) dichloride catalyst in DMF solvent. The expected product (5a) was formed in 79% yield. For Suzuki coupling, compound (4m) was treated with phenyl boronic acid in the presence of palladium acetate in tolune at 80 ^oC, the C-C coupled product (5b) was formed in excellent yield. Next, borylation²¹ was carried out using bis(pinacolato)diboron to synthesize compound (5c) in the presence of bis(triphenylphosphine)palladium(II) dichloride catalyst in toluene at 80 ^oC. Compounds with boronic acid group are extensively used in drug industry for producing various chemotherapeutic agents. We assume that compound (5c) can be easily converted to various boronic acid derivatives.²²

Our succeeding target was oxidation because polycyclic heteroaromatic compounds have been proved to be attractive intermediates for the synthesis of various best selling drugs.^1-5 To our surprise, 4-methyl-6,7-dihydrodibenzo[b,j][1,7] phenanthroline (4q) was oxidized and produced an aromatized compound (5d) when treated with SeO2 as oxidizing agent.²³ Based on this interesting result, we presume that all our newly synthesized compounds can be easily converted to aromatic molecules.

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SchemeII.C.3.2: Synthetic utility of 6,7-dihydro dibenzo [b,j][1,7]phenanthroline derivatives^a,b

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aAll the reactions were performed on a 1 mmol scale. ^bYields were refers to isolated and purified compounds.

Further, insertion of functional groups such as fluoro, bromo and chloro groups to 6,7-dihydrodibenzo [b,j] [1,7]phenanthroline (4a) would be beneficial for the productionofpharmaceutically importantandvaluable compounds, and also this strategy could widen the scope of all the newly synthesized molecules.Selectfluor is astable, nonvolatile, user-friendly reagent, widely used to introduce fluorine atoms into organiccompounds electrophilically.²⁴Recently, we reported the selective fluorination of isoxazoline N-oxides via C–C bond cleavage by usingSelectfluor.²⁵ When 6,7-dihydrodibenzo [b,j] [1,7]phenanthroline (4a) was treated with 1 equivalent of Selectfluor in acetonitrile at 80 ^oC, the reaction proceeded smoothly and compound 5e was formed in good yield. Similarly, NBS and NCS are the most extensively used electrophilic reagents for bromination²⁶ and chlorination,²⁷ respectively. When compound 4a was treated with 1 equivalent of NBS in acetonitrile at 80

oC, the expected product 5f was formed in 61% yield along with small amount of an aromatic compound (5g). The formation of 5g is due to the oxidizing property of NBS.

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Figure II.C.3.2:Crystal structure of compound 5f²⁸

On the otherhand, the reaction of 4a with 1 equivalent of NCS in acetonitrile at 80^oC, produced compound 5h as the sole product in 69% yield after 1h. Next, we examined the effect of 2 equivalents of NCS and NBS in the same reaction conditions. When compound 4a was treated with 2 equivalents of NCS, the reaction produced a geminal dichloride (5i) in good yield. However, when 2 equivalents of NBS was treated with compund4a, the reaction proceeded with simultaneous bromination and aromatization which produced an interesting compound 5h in moderate yield along with compound 5g in 34% yield. Conclusively, C-C coupling, borylation, aromatization and the possible addition of different functional groups (fluoro, bromo and chloro) means that our products could be structurally modified into valuable compounds (5a–5j), and so they might be useful for the development of new therapeutic agents in the future.

II.C.4. Conclusion

In conclusion, we have developed an efficient iron/acetic acid mediated intramolecular reductive cyclization protocol for the synthesis of novel group of 6,7-dihydrodibenzo[b,j][1,7]

phenanthroline derivatives, from easily available starting materials. The broad substrate scope and good to excellent yields of the products made this methodology interesting and applicable for industrial purposes. Further, we revealed that our compounds can be structurally modified to obtain various useful compounds for the development of new therapeutic agents.

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