Transition-Metal-Catalyzed Diarylation of Isocyanides with Triarylbismuthines for the Selective Synthesis of Imine Derivatives

The transition-metal-catalyzed diarylation of isocyanides with triarylbismuthines was investigated in detail, and rhodium catalysts such as [RhCl(nbd)]2 were found to selectively afford N-alkyl diaryl ketimines. On the other hand, palladium-catalyzed diarylation proceeded with the incorporation of two molecules of isocyanide, preferentially yielding N,N’-dialkyl or N,N’-diaryl α-diimines. In addition, a cascade synthesis of 2,3-diarylquinoxalines starting from the palladium-catalyzed diarylation of isocyanides with triarylbismuthines was successfully achieved.

However, it is unclear what factors would affect the product selectivity of α-diimines 3 and/or ketimines 5 using BiAr 3 . Hence, we investigated the transition-metal-catalyzed diarylation of isocyanides with BiAr 3 1 under several reaction conditions for the selective synthesis of imine derivatives (3 or 5) (Scheme 1c).

Results and Discussion
In our previous paper [42], we reported that Pd(OAc) 2 -catalyzed diarylation of isocyanides 2 with BiAr 3 1 selectively afforded α-diimines 3 (a representative result is shown in Table 1, entry 1). When the catalyst was changed to Pd(PPh 3 ) 4 , a typical zero-valent palladium complex, the yield of 3aa decreased significantly (entry 2). On the other hand, other divalent palladium complexes such as PdCl 2 and Pd(PPh 3 ) 2 Cl 2 selectively afforded 3aa with good yields (entries 3 and 4). Addition of PPh 3 to Pd(OAc) 2 resulted in lower yield of 3aa (entry 5). The zero-valent Pd complex, Pd 2 (dba) 3 , gave 3aa in moderate yield (entry 6). In the absence of a catalyst, barely any diarylation occurred (entry 7).
The reaction conditions for the Pd(OAc) 2 -catalyzed diarylation of 2a with 1a were also investigated in more detail (entries [8][9][10][11][12][13][14][15][16][17][18]. In all cases, α-diimine 3aa was obtained as the major product, mostly along with very small amounts of ketimine 5aa. Reducing the loading of 1a resulted in a decrease in the yield of 3aa (entry 8). The presence of air did not inhibit the formation of 3aa (entry 9). When the reaction was conducted at room temperature, the yield of 3aa decreased (entry 10). Decreasing the amount of Pd(OAc) 2 resulted in a gradual decrease in the yield of 3aa (entries 11 and 12). Among the solvents examined (entries [13][14][15][16], acetonitrile gave the best result, obtaining 3aa in 84% yield (entry 15). The present diarylation also proceeded even in a shorter time (4 h), affording 3aa in 81% yield (entry 17). A similar result was also obtained under Ar atmosphere as under air (entry 18 vs. 9).  Surprisingly, changing the catalyst to rhodium complexes selectively afforded ketimine 5aa without formation of 3aa (Table 2, entries 1-4). For example, the diarylation using [RhCl(nbd)]2 exclusively afforded 5aa in 50% yield (entry 1). Reducing the loading of this catalyst resulted in a lower yield of 5aa (entry 2). In addition, use of excess 1a improved the yield of 5aa with this catalyst (entry 3). RhH(CO)(PPh3)3, which is an active catalyst for hydroformylation, was ineffective when used for the present diarylation of isocyanide 2a (entry 4).
Since several rhodium complexes exhibited good ketimine selectivity, we next investigated the rhodium-catalyzed diarylation of tert-butyl isocyanide 2a with triphenylbismuthine 1a. The Rh-catalyzed diarylation was performed on a 0.4 mmol scale (1a and 2a) using [RhCl(nbd)] 2 , and the desired ketimine 5aa was obtained in 51% yield by adding (p-MeO-C 6 H 4 ) 3 P as the ligand (entry 5). The diarylation using 1.0 mL of C 6 H 6 improved the yield of 5aa to 71% yield (entry 7). Use of 0.6 mmol of 1a resulted in a slightly lower yield of 5aa (entry 9 vs. 7). Some other rhodium catalysts, such as RhCl(PPh 3 ) 3 3 , with no reaction taking place in most cases (these data are not shown in Table 2). Among the catalysts examined, trans-RhCl(CO)(PPh 3 ) 3 exhibited a moderate catalytic activity for the diarylation to give 5aa (entry 13). Overall, when mononuclear Rh complexes were used as catalysts, many byproducts were formed via polymerization of tert-butyl isocyanide. In contrast, this polymerization was suppressed by using [RhCl(nbd)] 2 . These results suggest that the choice of catalysts is very important for the selective reaction between isocyanides and BiAr 3 . catalysts, many byproducts were formed via polymerization of tert-butyl isocyanide. In contrast, this polymerization was suppressed by using [RhCl(nbd)]2. These results suggest that the choice of catalysts is very important for the selective reaction between isocyanides and BiAr3.
As mentioned above, the Pd and Rh catalysts were found to afford α-diimines 3 and ketimines 5, respectively, with excellent product selectivity. Conceivably, α-diimines 3 might be more important than ketimines 5 as synthetic intermediates. Hence, we examined the scope and limitations of this catalytic diarylation using the reaction conditions found in entry 1 of Table 1 (Scheme 3). In the cases of aliphatic isocyanides 2a-2d, the corresponding N,N'-dialkyl α-diimines 3aa-3ad were successfully obtained in good yields. The diarylation of electron-rich aromatic isocyanide 2e also afforded the corresponding N,N'-diaryl α-diimine 3ae in good yield, whereas aromatic isocyanides with electron-withdrawing groups such as p-nitro and p-cyano groups resulted in the formation of a complex mixture.
In addition, the scope and limitations of the triarylbismuthines were investigated (Scheme 4). The diarylation of t-BuNC 2a, with BiAr3 1b-1d was conducted, and the corresponding N,N'-di-tert-butyl α-diimines 3ba-3da were formed in moderate yields. When
With the optimal reaction conditions in hand ( Table 2, entry 7), the scope of the Rhcatalyzed diarylation of aliphatic isocyanides 2 with BiAr 3 1 was examined (Scheme 2). The reaction of t-BuNC 2a with BiPh 3 1a afforded 5aa in 71% yield, whereas cyclohexyl isocyanide 2c underwent the diarylation to provide 5ac in 40% yield. The reactions of t-BuNC 2a with p-Me, p-CF 3 , and p-Cl-substituted triarylbismuthines 1 also proceeded to give the corresponding N-tert-butyl diaryl ketimines (5ba, 5da, and 5fa) in moderate to good yields (see Materials and Methods).
As mentioned above, the Pd and Rh catalysts were found to afford α-diimines 3 and ketimines 5, respectively, with excellent product selectivity. Conceivably, α-diimines 3 might be more important than ketimines 5 as synthetic intermediates. Hence, we examined the scope and limitations of this catalytic diarylation using the reaction conditions found in entry 1 of Table 1 (Scheme 3). In the cases of aliphatic isocyanides 2a-2d, the corresponding N,N'-dialkyl α-diimines 3aa-3ad were successfully obtained in good yields. The diarylation of electron-rich aromatic isocyanide 2e also afforded the corresponding N,N'-diaryl αdiimine 3ae in good yield, whereas aromatic isocyanides with electron-withdrawing groups such as p-nitro and p-cyano groups resulted in the formation of a complex mixture.
The impact of reducing the catalyst loading was then examined to allow for the easy isolation of α-diimines 3 ( Table 4). The catalytic diarylation of isocyanide 2a was conducted using 5 mol% Pd(OAc)2 and one equivalent of triphenylbismuthine 1a to 2a under an atmosphere of N2, and α-diimine 3aa was obtained in low yield (entry 1). Interestingly, under an atmosphere of air, the yield of 3aa was dramatically improved (entry 2). Using molecular oxygen instead of air was also effective (entry 3). However, the combination of divalent copper salts was ineffective for the diarylation (entries 4 and 5). Moreover, the effect of reducing the amount of BiPh3 1a was examined (entries 6-8). Even when using 1/3 equivalent of 1a, α-diimine 3aa was obtained in satisfactory yield (entry 6). This clearly indicates that all three phenyl groups on 1a could be used for the formation of 3aa. When the loading of Pd(OAc)2 was reduced to 1 mol%, the yield of 3aa slightly decreased (entry 7). However, the use of 2 mol% of Pd(OAc)2 led to the formation of 3aa in a satisfactory yield (81%). As can be seen from the data in Table 4, the use of a combination of Pd(OAc)2 and air reduced the loading of both catalyst and triarylbismuthine. Further examination An equimolar reaction of 2a with 1c was found to afford ketimine 5ca in parallel to α-diimine 3ca (entry 1), while decreasing the amount of 1c resulted in the selective formation of 3ca (entry 3). Therefore, the molar ratio of 1c to 2a was an important factor for the selective synthesis of α-diimine 3ca.
The impact of reducing the catalyst loading was then examined to allow for the easy isolation of α-diimines 3 ( Table 4). The catalytic diarylation of isocyanide 2a was conducted using 5 mol% Pd(OAc) 2 and one equivalent of triphenylbismuthine 1a to 2a under an atmosphere of N 2 , and α-diimine 3aa was obtained in low yield (entry 1). Interestingly, under an atmosphere of air, the yield of 3aa was dramatically improved (entry 2). Using molecular oxygen instead of air was also effective (entry 3). However, the combination of divalent copper salts was ineffective for the diarylation (entries 4 and 5). Moreover, the effect of reducing the amount of BiPh 3 1a was examined (entries 6-8). Even when using 1/3 equivalent of 1a, α-diimine 3aa was obtained in satisfactory yield (entry 6). This clearly indicates that all three phenyl groups on 1a could be used for the formation of 3aa. When the loading of Pd(OAc) 2 was reduced to 1 mol%, the yield of 3aa slightly decreased (entry 7). However, the use of 2 mol% of Pd(OAc) 2 led to the formation of 3aa in a satisfactory yield (81%). As can be seen from the data in Table 4, the use of a combination of Pd(OAc) 2 and air reduced the loading of both catalyst and triarylbismuthine. Further examination of reaction conditions for the Pd(OAc) 2 -catalyzed diarylation in air revealed that acetonitrile was the best for the present diarylation [42].
In our previous paper, we proposed a possible pathway for the Pd(OAc) 2 -catalyzed diarylation of isocyanide 2 with triarylbismuthine 1 to afford α-diimine 3, the essence of which is shown in Scheme 5. of reaction conditions for the Pd(OAc)2-catalyzed diarylation in air revealed that acetonitrile was the best for the present diarylation [42]. In our previous paper, we proposed a possible pathway for the Pd(OAc)2-catalyzed diarylation of isocyanide 2 with triarylbismuthine 1 to afford α-diimine 3, the essence of which is shown in Scheme 5. Transmetalation between Pd(OAc)2 and BiAr3 1 might generate arylpalladium species I, into which isocyanide 2 inserts to form the imidoylpalladium species II. The subsequent ligand-exchange reaction of II with itself then leads to the palladium complexes III and IV. Reductive elimination from III affords the α-diimines 3 along with the Pd(0) Transmetalation between Pd(OAc) 2 and BiAr 3 1 might generate arylpalladium species I, into which isocyanide 2 inserts to form the imidoylpalladium species II. The subsequent ligand-exchange reaction of II with itself then leads to the palladium complexes III and IV. Reductive elimination from III affords the α-diimines 3 along with the Pd(0) species. Since the Pd(OAc) 2 -catalyzed diarylation proceeds smoothly in the presence of oxidizing agents such as air, the Pd(0) species might be oxidized to the Pd(II) species by air, or by the bismuth compounds present in the reaction system.
In the case of rhodium catalysts such as [RhCl(nbd)] 2 , oxidative addition of BiAr 3 1, followed by insertion of isocyanide 2 into the Rh-Ar bond results in the formation of an imidoylrhodium species. Presumably, the ligand-exchange reaction is less important for the imidoylrhodium species compared with the Pd(OAc) 2 -based system. Accordingly, transmetalation of imidoylrhodium species with BiAr 3 1 might generate aryl imidoylrhodium species of the type "ArC(=NR)-RhL n -Ar," and the subsequent reductive elimination might selectively afford ketimines 5.
Since α-diimines 3 are expected to be important precursors for the synthesis of nitrogencontaining heterocyclic compounds, an attempt was also made to synthesize nitrogencontaining heterocycles without purification of α-diimines 3 prepared by the Pd(OAc) 2catalyzed diarylation of isocyanides with triarylbismuthines. Hence, we next examined the synthesis of quinoxaline derivatives (Scheme 6). Scheme 6. Application to cascade synthesis of 2,3-diarylquinoxalines.
After the catalytic diarylation of t-BuNC 2a with BiAr 3 1a was complete, the reaction mixture was filtered through a Celite pad. The filtrate was then treated with 1 N HCl aq., followed by the addition of o-phenylenediamine 8a. The mixture was heated at 60 • C for 12 h to successfully afford the corresponding quinoxaline derivative 9a in high yield. 4,5-Dimethyl-substituted o-phenylenediamine 8b also reacted with the α-diimine 3aa formed in situ to give the quinoxaline 9b in high yield. In the case of o-phenylenediamine 8c, which has an electron-withdrawing nitro group, the corresponding quinoxaline 9c was formed in moderate yield. Moreover, when BiAr 3 compounds with p-methylor p-fluorogroups were employed for this cascade synthesis, the corresponding quinoxalines 9d and 9e, respectively, were obtained in good yields. The present method of quinoxaline synthesis is very convenient, because the α-diimines 3 formed in situ can be used directly without purification.

Typical Reaction Procedure for Ketimine Synthesis
In a dried 10 mL Schlenk test tube, norbornadiene rhodium(I) chloride dimer (0.04 mmol) and (p-MeOC 6 H 4 ) 3 P (0.08 mmol) were dissolved in benzene (1.0 mL), and the mixture was stirred for 10 min at room temperature under Ar atmosphere. Then, triarylbismuthine (1; 0.4 mmol) and isocyanides (2; 0.4 mmol) were added to the reaction mixture. The resulting mixture was heated at 70 • C for 18 h. After the reaction, the crude product was filtered through a Celite pad using AcOMe as the eluent. All volatiles were evaporated under reduced pressure, and the yields of corresponding ketimines were determined by 1 H NMR spectroscopy (solv.: CDCl 3 , internal standard: 1,3,5-trioxane) [43].
In this synthetic method, ketimine can be synthesized in a highly selective manner, and the purity is high even in the crude state. However, when treated with recycled GPC to remove unreacted starting substrates, the ketimine undergoes hydrolysis to produce a small amount of the corresponding ketone. Therefore, in order to use this ketimine synthesis method effectively, it is recommended to use it in one pot without isolating the ketimine. Ketimine 5da and 5fa could be isolated by recycled GPC (CH 2 Cl 2 ), and their characterization data are shown as follows ( 1 H and 13

Typical Reaction Procedure for α-Diimine Synthesis (Schemes 3 and 4)
Triphenylbismuthine (1a; 0.4 mmol) and tert-butyl isocyanide (2a; 0.4 mmol) were dissolved in benzene (2 mL) in a dried two-necked test tube under a N 2 atmosphere. Palladium diacetate (0.08 mmol) was added to the mixture. The resulting mixture was stirred for 18 h at 70 • C. After the reaction, the crude product was filtered through a Celite pad. All volatiles were evaporated under reduced pressure, and the NMR spectrum was measured (solv.: CDCl 3 ). Dioxane was used as an internal standard. 1

Conclusions
In this study, we describe in detail the transition-metal-catalyzed diarylation of isocyanides with triarylbismuthines. When rhodium complexes were used as the catalyst in the diallylation reaction, ketimines (with one molecule of isocyanide incorporated) were highly selectively formed, whereas when palladium-based catalyst was used, α-diimines (with two molecules of isocyanide incorporated) were formed preferentially. For the purpose of further elucidating the details of this catalytic system, the effects of catalyst, solvent, and reaction temperature on the diarylation were investigated in detail to optimize the reaction conditions and determine the byproducts. Furthermore, the palladium-catalyzed diarylation was successfully applied to the cascade synthesis of quinoxalines via the formation of α-diimines as key intermediates.