Development of a New Arylamination Reaction Catalyzed by Polymer Bound 1,3-(Bisbenzimidazolyl) Benzene Co(Ii) Complex and Generation of Bioactive Adamanate Amines

: We herein report the preparation and characterization of an inexpensive polymer supported 1,3-bis(benzimidazolyl)benzeneCo(II) complex [PS-Co(BBZN)Cl 2 ] as a catalyst by using the polymer (divinylbenzene cross-linked chloromethylated polystyrene), on which 1,3-bis(benzimidazolyl) benzeneCo(II) complex (PS-Co(BBZN)Cl 2 ) has been immobilized. This‘catalyst was employed to develop arylamination reaction and robustness of the same reaction was demonstrated by synthesizing various bioactive adamantanyl-tethered-biphenylamines. Our synthetic methodology was much improved than reported methods due to the use of an inexpensive and recyclable catalyst.


Introduction
Transition metal-catalyzed cross-coupling reactions between aryl halides and primary/secondary amines to obtain aminated aryl compounds has been an area of interest due to the wide applications of arylamines in the synthetics and pharmaceutical industries [1][2][3][4][5]. In this direction, the Buchwald-Hartwig cross-coupling reaction was performed by using transition metal catalysts, ligands and bases disadvantage of this reaction is the use of expensive catalysts, which offers the chemist the opportunity to discover cheaper, reusable catalysts to drive the arylamination reactions. Inspired by major developments in cobalt-catalyzed arylamination reactions, we developed a complementary method to perform an arylamination reaction using cobalt as a metal catalyst [9][10][11] In addition, benzimidazole ligand coordinated metal complexes are widely used as catalysts in arylamination reactions [12]. Since these catalysts were found to be less hydrophobic, immobilization of such metal complexes with polymer support was observed to be stable, selective, and recyclable, attributed to the steric, electrostatic, hydrophobic and conformational effects of the polymer support [13]. Hence, several reports pertaining to the synthesis of arylamines using polymer-supported transition metal complexes are found [14][15][16]. Specifically, chloromethylated polystyrene cross-linked with divinyl-benzene was employed as a macromolecular support to perform the arylamination reactions [17][18][19][20][21][22].
In medicinal chemistry, an adamantane-coupled bicyclical core structure was used as an important pharmacophore, which was inserted in many drugs [23]. Hence, the adamantane structure was recognized as a readily available "liphophilic bullet" for providing critical liphophilicity to known pharmacophoric units. Given the remarkable importance of adamantane chemistry, we recently reported the synthesis and biology of adamantyl-tethered biphenylic compounds as potent anticancer agents [24]. In our continued efforts to synthesize newer bioactive agents [25][26][27][28][29][30][31], we herein report a practical, economically feasible and efficient arylamination reaction using polymer-supported 1,3-bis(benzimidazolyl)benzeneCo(II) complex (PS-Co(BBZN)Cl2) as a catalyst. Interestingly, the recovered (PS-Co(BBZN)Cl2) could be reused three times without a significant loss of activity.

Chemistry of Catalyst Design and Method Development
We initially synthesized polymer-supported 1,3-bis(benzimidazolyl)benzeneCo(II) complex [PS-Co(BBZN)Cl2] as shown in Scheme 1. For this, 1, 3-bis(benzimidazolyl)benzene was treated with chloromethylated polystyrene divinylbenzene and followed by the addition of cobalt chloride. The obtained PS-Co (BBZN)Cl2 was characterized by analytical techniques including CHNS, UV-Vis, FT-IR, SEM-EDX and TGA as presented in supporting information (Figure 1, Supplementary SI-02). Based on N% and Co% obtained through elemental and metal ion analysis, the complex formed on the polymer support was about 0.0053 moles per 1 g of the polymer support which corresponded to 7.16% of Co intake. This further confirmed the formation of the complex on the polymer support. For this, 1, 3-bis(benzimidazolyl)benzene was treated with chloromethylated polystyrene divinylbenzene and followed by the addition of cobalt chloride. The obtained PS-Co (BBZN)Cl 2 was characterized by analytical techniques including CHNS, UV-Vis, FT-IR, SEM-EDX and TGA as presented in supporting information (Figure 1, Supplementary SI-02). Based on N% and Co% obtained through elemental and metal ion analysis, the complex formed on the polymer support was about 0.0053 moles per 1 g of the polymer support which corresponded to 7.16% of Co intake. This further confirmed the formation of the complex on the polymer support. Motivated by the increased understanding of the Co-catalyzed amination reaction, we next investigated the applicability of (PS-Co (BBZN)Cl2) in the arylamination reaction. To examine this hypothesis, 1-(5-bromo-2-methoxyphenyl)adamantine (1a) and 4-chloro aniline (2a) were selected as model substrates and reagents for the reaction in 1,4-dioxane media and Cs2CO3 as a base (Scheme 2). Scheme 2. General scheme of arylamination reaction between adamantane bromide and various amines using PS-Co(BBZN)Cl2 as a catalyst.
Control experiments established the importance of both PS-Co(BBZN)Cl2 and ligand, as no product was obtained (Table 1, entry 1). Gratifyingly, the substrate was transformed into the desired product 3-(adamantan-1-yl)-N-(4-chlorophenyl)-4-methoxyaniline (3a) with 51% yield in the presence of catalyst (PS-Co(BBZN)Cl2) (10 mol%) and ligand L3 (Table 2, entry 10). Screening of various classes of ligands ( Figure 2) to improve the yield revealed that the use of phosphine based ligand BINAP (L3) or Xphose (L4) gave improved yields at different catalyst concentrations (Table 1, entry 10, 11, 14, 15), whereas the other ligands such as bidentate ligands (L1, L2) and N-heterocyclic carbine ligands (L5, L6) yielded no products indicating the high role of selectivity of ligands in the forward reaction. The most robust reaction was achieved by the use of 12 mol% of PS-Co(BBZN)Cl2 in the presence of BINAP with an 86% yield at 10 h reaction condition (Table 1, entry 14). Further investigation revealed that there was no considerable improvement in yield when the catalyst load was increased to 15 mol% (Table 1, entry 18, 19) whereas the yield dropped to 69% when the reaction time was reduced to 6 h with 15 mol% catalyst (Table 1, entry 20). Using the above better protocol, we further synthesized ABTAs by reacting adamantine bromo compounds (1a) and various amines ( Table 2). It was observed that all amine partners productively coupled with good yields of around 70-86%.  Motivated by the increased understanding of the Co-catalyzed amination reaction, we next investigated the applicability of (PS-Co (BBZN)Cl 2 ) in the arylamination reaction. To examine this hypothesis, 1-(5-bromo-2-methoxyphenyl)adamantine (1a) and 4-chloro aniline (2a) were selected as model substrates and reagents for the reaction in 1,4-dioxane media and Cs 2 CO 3 as a base (Scheme 2). Motivated by the increased understanding of the Co-catalyzed amination reaction, we next investigated the applicability of (PS-Co (BBZN)Cl2) in the arylamination reaction. To examine this hypothesis, 1-(5-bromo-2-methoxyphenyl)adamantine (1a) and 4-chloro aniline (2a) were selected as model substrates and reagents for the reaction in 1,4-dioxane media and Cs2CO3 as a base (Scheme 2). Scheme 2. General scheme of arylamination reaction between adamantane bromide and various amines using PS-Co(BBZN)Cl2 as a catalyst.
Control experiments established the importance of both PS-Co(BBZN)Cl2 and ligand, as no product was obtained ( Table 1, entry 1). Gratifyingly, the substrate was transformed into the desired product 3-(adamantan-1-yl)-N-(4-chlorophenyl)-4-methoxyaniline (3a) with 51% yield in the presence of catalyst (PS-Co(BBZN)Cl2) (10 mol%) and ligand L3 (Table 2, entry 10). Screening of various classes of ligands ( Figure 2) to improve the yield revealed that the use of phosphine based ligand BINAP (L3) or Xphose (L4) gave improved yields at different catalyst concentrations (Table 1, entry 10, 11, 14, 15), whereas the other ligands such as bidentate ligands (L1, L2) and N-heterocyclic carbine ligands (L5, L6) yielded no products indicating the high role of selectivity of ligands in the forward reaction. The most robust reaction was achieved by the use of 12 mol% of PS-Co(BBZN)Cl2 in the presence of BINAP with an 86% yield at 10 h reaction condition (  entry 20). Using the above better protocol, we further synthesized ABTAs by reacting adamantine bromo compounds (1a) and various amines ( Table 2). It was observed that all amine partners productively coupled with good yields of around 70-86%. Control experiments established the importance of both PS-Co(BBZN)Cl 2 and ligand, as no product was obtained ( Table 1, entry 1). Gratifyingly, the substrate was transformed into the desired product 3-(adamantan-1-yl)-N-(4-chlorophenyl)-4-methoxyaniline (3a) with 51% yield in the presence of catalyst (PS-Co(BBZN)Cl 2 ) (10 mol%) and ligand L3 (Table 2, entry 10). Screening of various classes of ligands ( Figure 2) to improve the yield revealed that the use of phosphine based ligand BINAP (L3) or Xphose (L4) gave improved yields at different catalyst concentrations (Table 1, entry 10, 11, 14, 15), whereas the other ligands such as bidentate ligands (L1, L2) and N-heterocyclic carbine ligands (L5, L6) yielded no products indicating the high role of selectivity of ligands in the forward reaction. The most robust reaction was achieved by the use of 12 mol% of PS-Co(BBZN)Cl 2 in the presence of BINAP with an 86% yield at 10 h reaction condition (  entry 20). Using the above better protocol, we further synthesized ABTAs by reacting adamantine bromo compounds (1a) and various amines ( Table 2). It was observed that all amine partners productively coupled with good yields of around 70-86%.
All novel compounds exhibited spectral properties consistent with the assigned structures and were fully characterized by their spectroscopic data (mass, elemental, 1 H and 13 C NMR analysis).
The majority of reactions were done by keeping time point for 16 h and when the concentration of the catalyst was increased to 12%, the reaction was completed in 12 h and in many cases pure product was produced with excellent yield. The above developed method tolerated the presence of substituent in the aromatic amino-compounds. Specifically, we observed that the electron-donating para-substituted aromatic amine partners were well-tolerated to produce corresponding products in good to excellent yields ( Table 2, entries 1-12). However, ortho-substituted and electron-withdrawing group bearing compounds were not productive giving lower yields (Table 2, entries 5, 11, 12, 13).        (1 mmol (1 mmol                  With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic Halo Compounds Amine Product a and Yield (%) 1 With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.
With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.
With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry
Aromatic With the reaction conditions established we tried to investigate the scope of the new protocol on different substituted aromatic bromo compounds by treating with various amines (Table 3). We found that electron donating para-substituted on aromatic halo partner was tolerated well to give corresponding products in good to excellent yields (entries 1, 2, 3 and 5), but with ortho-substituted and electron-withdrawing group bearing aromatic bromo compounds observed a loss in yield (entries 4, 6 and 7) with no improvement in the reaction conversion on prolonged reaction. Table 3. Various substrates and reagents used to optimization of arylamination reaction.

Entry Aromatic Halo Compounds Amine Product a and Yield (%)
were fully characterized by their spectroscopic data (mass, elemental, 1 H and 13 C NMR analysis). It was found that the use of a catalyst PS-Co(BBZN)Cl2, in combination with some ligands provided a robust catalytic system. On the basis of previous mechanistic studies in cobalt-catalyzed C−N bond formation reactions, it was possible to propose a mechanism for the conversion of 3-(adamantan-1-yl)-N-(4-chlorophenyl)-4-methoxyaniline (3 a) as shown in Figure 3 [32][33][34].  Initially, the catalyst makes a complex with amine to form a catalyst-amine complex A, which undergoes an oxidative addition reaction with 1-(5-bromo-2-methoxyphenyl)adamantane and complex B formation occurs. Complex B reacts with cesium carbonate base and undergoes metathesis step, which gave complex C. Finally, the reductive elimination reaction complex C takes place and thereby catalyst regeneration and the desired product formation occur in the last step ( Figure 3).
Further, we performed density-functional theory calculations using dispersion corrected CAM-B3 LYP functional and 6-31+G method [35]. All electron basis set as implemented in the Gaussian 09 package [36]. The minima nature of the structures has been confirmed based on computed real harmonic vibrational analysis at the same level of theory. Gibbs free energy calculations for four intermediate cobalt complexes were chosen for our mechanistic elucidation. Initially CoCl 2 makes the coordination complex with the ligand and reacts with aromatic amine and forms Co-NH bond quickly

Recyclability of the Catalyst
Further, the superiority of PS-Co(BBZN)Cl2 catalyst was its recyclability, which was investigated by using the compound 1 a and 2 b as a model reaction. After each run, the catalyst was filtered off and washed with water followed by methanol, it was then dried in an oven at 120 °C for 15 min and used directly for the next reaction. The results were summarized (Table 4). We recorded that the catalyst could be used thrice and isolated yields achieved were above 70%.

Preparation of BBZN Functionalized Polymer Support
The chloromethylated polystyrene beads cross-linked with 6.5% divinylbenzene were first washed with a mixture of THF and water in the ratio 4:1 using Soxhlet extractor for 48 h. The beads were then vacuum dried. The chloromethylated polystyrene beads (3 g) were allowed to swell in DMF solution of BBZN ligand (5.2 g) was added to the above suspension followed by the addition of triethylamine (12 mL) in ethylacetate (105 mL) and was heated at 60 °C for 45 h in a water bath. It was cooled to room temperature, filtered, and washed with DMF. The beads were then Soxhlet extracted with ethanol to remove any unreacted BBZN and dried in an oven at 60 °C overnight.

Recyclability of the Catalyst
Further, the superiority of PS-Co(BBZN)Cl 2 catalyst was its recyclability, which was investigated by using the compound 1 a and 2 b as a model reaction. After each run, the catalyst was filtered off and washed with water followed by methanol, it was then dried in an oven at 120 • C for 15 min and used directly for the next reaction. The results were summarized (Table 4). We recorded that the catalyst could be used thrice and isolated yields achieved were above 70%.

Recyclability of the Catalyst
Further, the superiority of PS-Co(BBZN)Cl2 catalyst was its recyclability, which was investigated by using the compound 1 a and 2 b as a model reaction. After each run, the catalyst was filtered off and washed with water followed by methanol, it was then dried in an oven at 120 °C for 15 min and used directly for the next reaction. The results were summarized (Table 4). We recorded that the catalyst could be used thrice and isolated yields achieved were above 70%.

Preparation of BBZN Functionalized Polymer Support
The chloromethylated polystyrene beads cross-linked with 6.5% divinylbenzene were first washed with a mixture of THF and water in the ratio 4:1 using Soxhlet extractor for 48 h. The beads were then vacuum dried. The chloromethylated polystyrene beads (3 g) were allowed to swell in DMF solution of BBZN ligand (5.2 g) was added to the above suspension followed by the addition of triethylamine (12 mL) in ethylacetate (105 mL) and was heated at 60 °C for 45 h in a water bath. It was cooled to room temperature, filtered, and washed with DMF. The beads were then Soxhlet extracted with ethanol to remove any unreacted BBZN and dried in an oven at 60 °C overnight.

Preparation of BBZN Functionalized Polymer Support
The chloromethylated polystyrene beads cross-linked with 6.5% divinylbenzene were first washed with a mixture of THF and water in the ratio 4:1 using Soxhlet extractor for 48 h. The beads were then vacuum dried. The chloromethylated polystyrene beads (3 g) were allowed to swell in DMF solution of BBZN ligand (5.2 g) was added to the above suspension followed by the addition of triethylamine (12 mL) in ethylacetate (105 mL) and was heated at 60 • C for 45 h in a water bath. It was cooled to room temperature, filtered, and washed with DMF. The beads were then Soxhlet extracted with ethanol to remove any unreacted BBZN and dried in an oven at 60 • C overnight.

Preparation of PS-Co(BBZN)Cl 2 Complex
The functionalized beads (1.0 g) were allowed to swell in 50 mL acetonitrile and toluene mixture in the ratio 1:1 for 1 h. Then the solvent was decanted. To this, 1.426 g of CoCl 2 .6 H 2 O dissolved in methanol (100 mL) was added at intervals (4 times) and heated at 60 • C for 48 h. It was filtered, washed with alcohol and Soxhlet extracted to remove any unreacted CoCl 2 .6 H 2 O. It was filtered and dried in an oven at 60 • C for 10 h and vacuum dried.

General Procedure for (PS-Co(BBZN)Cl 2 ) Complex Catalyzed C−N Bond-Formation Reaction
A dried Schlenk tube was charged with substrate 1 a (320 mg, 1 mmol), 2 a (127.6 mg, 1 mmol), BINAP (48 mg, 15 mol%), (PS-Co(BBZN)Cl 2 ](38 mg, 12 mol%). The tube was evacuated and backfilled with N 2 , and Cs 2 CO 3 (975 mg, 3 mmol) followed by reagent grade 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 • C for 10 h. After completion of reaction the mass was cooled to room temperature, filtered off the catalyst, the solvent quenched with water and diluted with ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with (5 mL) ethyl acetate. The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulphate and the solvent was removed in vacuum. The crude product was purified using silica gel column chromatography.