B. D. Jadhav and
S. K. Pardeshi*
Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Ganeshkhind, Pune – 411007, India. E-mail: skpar@chem.unipune.ac.in; Fax: +91 020 25691728; Tel: +91 020 25601225 extn 514
First published on 28th January 2016
In present work, an efficient Cu(OAc)2·H2O catalyzed protocol in the absence of any additional ligand has been developed for the N-arylation of amines and nitrogen containing heterocycles using trivalent organobismuth reagents under mild conditions. This protocol tolerates a variety of functional groups on amines and the organobismuth reagent with a high degree of chemoselectivity.
It is noted that simple inorganic copper(II) salts without extra ligands for catalyzing such coupling reactions is of limited scope.18 There are few reports on the amination of aryl halides with amines promoted by copper(II) salts without using organic ligands, they often required large amounts of Cu(OAc)2 (ref. 18a and b) or copper oxide nanoparticles,18c which raised the cost of the reaction. Choudary and coworkers reported an efficient catalytic N-arylation reaction using the copper(II) apatite as the catalyst but require high catalyst loading.18d To this end, the development of a simple, easily available, economical copper catalyst with a low catalyst loading in the absence of any additional ligands for such coupling reactions would be highly demanding.
As a carbon source, we focused on the low toxic organobismuth compounds19 for use in copper-mediated C–N bond formation with amines and imides. N-Phenylation of aliphatic and aromatic amines by Ph3Bi under copper salt catalysis giving moderate yield of mono or diphenylated amines under mild conditions was reported by Barton et al.20 Good yields of mono and diphenylated derivatives was achieved in presence of metallic copper at room temperature but substrate scope is limited. In another study Finet et al.21 used triphenylbismuth diacetate as aryl source which reacts with various N–H containing heteroarenes in the presence of a catalytic amount of copper diacetate to afford moderate yields of the N-phenyl heteroarenes. Indoles are C3 or N-phenylated by triphenylbismuth bis-trifluoroacetate under copper catalyst.22 Combes and Finet23 reported reaction of triarylbismuthanes with iodobenzene diacetate in DCM under mild, neutral conditions to afford triarylbismuth diacetates, which can be isolated in good yields. The reagents can also be directly used in a one-pot copper catalyzed N-arylation of anilines to give near quantitative yields of the corresponding diarylamines. Various hydrazine derivatives were studied with respect to arylation by triarylbismuthane and triarylbismuth diacetate reagents with emphasis on scope and limitations by Tsubrik et al.24 Among these reagents, a few contained bulky substituents in their aromatic rings and substrates spanned a range from simple hydrazides to triply protected hydrazines. Organobismuth derivatives of pyrocatechol fragment for arylation of piperazines using copper acetate as catalyst in DCM was reported by Vassileva et al.25 which was used to synthesize eltoprazine [l-(2,3-dihydro-1,4-benzodioxine-5-yl)-piperazine] a potential anxiolytic and antidepressant drug. Recently copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides was reported by Sueda et al.26 which was utilized to synthesize 4-amino-1,2,3-triazole. In above cases they combined the corresponding trivalent and in few cases pentavalent organobismuth compounds with a stoichiometric amount of copper salt. Recently Petiot et al.27 used copper catalyzed N-arylation of azoles and diazoles using functionalized organobismuth(III) reagents. In addition they extended this protocol to N-arylate protected tryptophan derivatives promoted by a substoichiometric amount of copper acetate.
In this paper, we report a simple reagent system consisting of the easily accessible organobismuth(III) reagents and copper diacetate which catalyzes the N-arylation of various amines and N-heteroarenes in absence of any ligand. Optimization of reaction parameters such as amount of catalyst, role of bases, role of solvents, role of oxygen and mole ratio of organobismuth(III) reagents is also studied.
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Scheme 1 Optimization of reaction conditions for the N-phenylation of imidazole 1 with triphenylbismuthine. |
Among the tested copper salts, Cu(OAc)2 was found to be the best catalyst, which afforded 85% yield of 1-phenyl imidazole (3l) in presence of Cs2CO3 as base for 12 h at 80 °C (Table 1, entry 3). Cu powder and CuI giving 3l in moderate yields (Table 1, entries 2 and 4), but Cu powder catalyst require acetic acid as non aqueous reaction medium. In case of CuSO4 and CuO, poor yield of 3l was obtained (Table 1, entries 1 and 7). CuBr, and CuCl catalyst are more efficient than CuSO4 and CuO produced 35% and 25% yields of 3l (Table 1, entries 5 and 6). It is interesting to note that in CuBr catalysis cleavage of CAr–Bi bonds resulted in self coupling of triphenyl bismuthine giving isolated biphenyl in 45% yield along with 35% yield of N-phenyl imidazole using column chromatographic separation. Since CuBr and CuCl are more expensive and oxidizes very readily, so their use in C–N cross coupling is avoided. Hence the most efficient, inexpensive, and air-stable Cu(OAc)2 was selected as the catalyst for all further reactions. It has been found that 1.5 mmol copper acetate catalyst under optimized reaction conditions provide excellent yields. Controlled experiment conducted in the absence of catalyst indicate no desired C–N cross coupled product (Table 1, entry 8) the only detected and separated products were unreacted starting material and small amount of biphenyl formed due to self coupling of organobismuthine, which is known reactivity of organobismuthine under metal catalysis.
Entry | Base | Reaction time (h) | Yieldb (%) |
---|---|---|---|
a Reaction conditions: catalyst (1.5 mmol), triphenyl bismuthine (1 mmol), imidazole (1.2 mmol), base (2 mmol).b Isolated yields. | |||
1 | KOH | 12 h | 68 |
2 | K2CO3 | 12 h | 75 |
3 | K3PO4 | 12 h | 25 |
4 | CsF | 12 h | 20 |
5 | Cs2CO3 | 12 h | 85 |
6 | NaOH | 12 h | 35 |
7 | KF | 12 h | 45 |
8 | TEA | 12 h | 65 |
9 | — | 12 h | No reaction |
The study shows that, the reaction proceeds smoothly in presence of Cs2CO3 which gives 85% yield of N-phenyl imidazole (Table 2, entry 5). Other bases namely K3PO4, CsF and NaOH afforded low yields of 3l (Table 2, entries 3, 4 and 6). KOH and K2CO3 are other better choices in C–N cross coupling which gives excellent yields (Table 2, entries 1 and 2). In case of TEA, moderate yield of C–N cross coupled product was obtained (Table 2, entry 8). The coupling reaction does not proceed in the absence of base (Table 2, entry 9).
Entry | Solvent | T (°C) | Yieldb (%) |
---|---|---|---|
a Reaction conditions: catalyst (1.5 mmol), triphenyl bismuthine (1 mmol), imidazole (1.2 mmol), Cs2CO3 (2 mmol), 12 h.b Isolated yields.c Catalyst loading (2 mmol). | |||
1 | DMF | 120 | 40 |
2 | DMSO | 120 | 35 |
3 | C6H5CH3 | 120 | 55c |
4 | MeCN | 80 | 10 |
5 | DCM | 80 | 65c |
6 | THF | 80 | 85 |
7 | THF | 50 | 45 |
8 | THF | 60 | 60 |
9 | THF | 70 | 70 |
10 | H2O | 100 | 0 |
11 | MeOH | 80 | 0 |
As seen from Table 3, the reaction proceeds in both non-polar and polar solvent with significant variation in yield. C6H5CH3 and DCM which are non polar solvents favored the formation of 3l and gives moderate yield (Table 3, entries 3 and 5) but require high catalyst loading (2 mmol). THF gave the best results with Cs2CO3 as base at 80 °C (Table 3, entry 6) with 0.5 mmol copper catalyst. In case of MeCN, very poor yield of N-phenyl imidazole (3l) was obtained at 80 °C (Table 3, entry 4). With increase in polarity of solvents, the cleavage of the CAr–Bi bond was found to be enhanced, and in DMF (Table 3, entry 1) the predominant product was the homo coupled biphenyl along with 3l. When reactions were conducted with optimal solvent, THF at 70 °C, 60 °C and 50 °C decrease in yield of N-phenyl imidazole was noticed (Table 3, entries 7, 8 and 9). In H2O and MeOH under reflux (Table 3, entry 10 and 11), no C–N cross coupling was observed instead white suspension got accumulated on the inner walls of the reaction flask suggesting the decomposition of triphenyl bismuthine to bismuth hydroxide.
It is worth mentioning that, the reaction temperature, 110–130 °C which was proved to be necessary for other Cu-catalyzed N-arylations of amines and N-heterocycles with aryl halides, our catalytic system reduce reaction temperature to 80 °C.
Entry | Ph3Bi (mmol) | Cu(OAc)2 (mmol) | Atm. | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: triphenyl bismuthine, imidazole (1.2 mmol), Cs2CO3 (2 mmol) in 5 mL THF.b Isolated yields.c Reaction was conducted in 50 mL flask. | ||||
1 | 1.0 | 1.5 | Air | 90 |
2 | 1.0 | 1.5 | O2 | 85 |
3 | 1.0 | 1.5 | N2 | 70 |
4 | 0.7 | 1.5 | Air | 81 |
5 | 0.33 | 1.5 | Air | 50 |
6 | 1.0 | 1.0 | Air | 70 |
7 | 1.0 | 1.5 | Air | 65c |
8 | 1.0 | 0.5 | Air | 55 |
9 | 1.0 | 0.1 | Air | 30 |
On reacting 1.0 mmol of triphenylbismuth with imidazole (1l) in the presence of 1.5 mmol of copper acetate and 2.0 mmol of Cs2CO3 under air atmosphere, we obtained 3l in 90% yield (Table 4, entry 1). When the reaction was carried out under same stoichiometric ratio but in the pure O2 atmosphere, 85% yield was noticed (Table 4, entry 2). To validate the importance of oxygen, we performed the reaction under nitrogen atmosphere and noticed a drop in the yield of 3l (Table 4, entry 3) thereby suggesting the role of air/O2 during catalytic cycle under Cu-acetate. In addition when the reaction was carried out in a two neck round bottom flask of 50 mL capacity wherein more space existed due to which the yield was depressed, thus reflecting effect of molecular oxygen on reaction (Table 4, entry 7). The detail explanation is given in discussion part of mechanism. When 0.5 mmol of copper acetate was used, it has been found that the yield was further decreased up to 55% (Table 4, entry 8). However, further reduction in the catalyst loading was not tolerated where merely 30% yield of desired product was obtained (Table 4, entry 9).
To evaluate the transferability of second aryl group from the triphenylbismuthane, we performed the reaction using 0.7 mmol and observed a significant drop in yield of N-phenyl imidazole (Table 4, entry 4). This clearly indicates only one aryl group can be transferred from triarylbismuthane. Further reduction in mole ratio of triphenylbismuthine (0.33 mmol) delivers only 50% yield of product (Table 4, entry 5) which also supports above observation. This phenomenon is well known in copper catalysis involving organobismuth reagents.27,28 From above results it has been concluded that, the yield of N-phenylated product was dependent upon the amount of Cu(OAc)2.
Hence the optimum conditions for cross-coupling reactions in THF consist of the combination of Cu(OAc)2 (1.5 mmol) and Cs2CO3 (2.0 mmol) at 80 °C for 12 h without protection of air. The reactions were monitored by TLC as well as by the color change from the initial deep blue to turquoise green, with the simultaneous precipitation of grayish Cu(I) salt.
After optimizing the reaction conditions, the reaction scope was extended with electronically different anilines and triphenyl bismuthine (Scheme 2).
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Scheme 2 N-Arylation of amines (1a–f), amides (1g–h), sulphonamine (1k), imidazole (1l) and indole (1m) using triphenylbismuthane (2a). |
We chose several nitrogenated compounds possessing various functional groups for our study. Typical results are summarized in Table 5.
Entry | Amine R (1) | N-Arylated product (3) | Yieldb (%) |
---|---|---|---|
a Conditions: amine (1.0 mmol), Ph3Bi (1.2 mmol), Cu(OAc)2, (1.5 mmol), Cs2CO3 (2.0 mmol), THF (5 mL), 80 °C, 12 h.b Isolated yields.c Reaction was carried out by p-tolylbismuthine (2d). | |||
1 | H (1a) | 3a | 78 |
2 | p-Br (1b) | 3b | 70 |
3 | p-Cl (1c) | 3c | 65 |
4 | p-NO2 (1d) | 3d | 65 |
5 | p-OCH3 (1e) | 3e | 88 |
6 | p-CH3 (1f) | 3f | 86 |
7 | C6H5CO (1g) | 3g | 45 |
8 | CH3CO (1h) | 3h | 32 |
9 | ![]() |
3i | — |
10 | ![]() |
3j | — |
11 | ![]() |
3k | 40 |
12 | ![]() |
3l | 80 |
13c | (1l) | 3m | 75 |
14 | ![]() |
3n | 75 |
As illustrated in Table 5, aniline was monoarylated successfully using triphenyl bismuthine (Table 5, entry 1). Aromatic amines bearing either electron donating groups (Table 5, entry 6) or electron withdrawing groups (Table 5, entries 4 and 5) gave corresponding unsymmetrical diarylamines in good yield. Notably, halo substituent on the aryl amine remained unaffected under these reaction conditions. Thus, reaction of p-bromoaniline with triphenyl bismuthine gives desired secondary amine in good yield (Table 5, entry 2). Imidazole and indole was cross-coupled with triphenyl bismuthine affording excellent yields of corresponding N-phenyl derivatives (Table 5, entries 12 and 14). Imidazole on coupling with p-tolylbismuthine provides 75% yield of 1-p-tolyl-1H-imidazole thereby suggesting the effect of methyl substituent on cross coupling yield (Table 5, entry 13c).
The few reported methods to arylate amides and imides using the organobismuth alone, or in the presence of copper, either failed completely or gave very unsatisfactory yields. Almost all of these reactions require the use of high temperatures, very basic conditions, and long reaction time. For amide substrates such as benzamide and acetamide the N-phenylation under present reaction conditions produces low yields (45% and 32%) of N-arylated products (Table 5, entries 7 and 8). p-Toluenesulfonamide afforded the corresponding N-arylated product in 40% yield (Table 5, entry 11). Attempts with both aliphatic and aromatic secondary amines (Table 5, entries 9 and 10) were unsuccessful.
The catalytic activity of this protocol under optimized condition was evaluated with electronically different substituted bismuthines and phthalimide as per Scheme 3.
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Scheme 3 Steric and electronic effects of functionalized organobismuthanes (2a–g) on the N-arylation of 4. |
The results are summarized in Table 5.
It has been observed from Table 6 that, in copper-catalyzed reactions, the steric hindrance of the organobismuth reagent plays a significant role, probably at the stage of the transmetallation from bismuth to copper. When this transfer is very easy (by coordination of the copper species with an amine), the steric effect induces less important consequences. Most of bismuthines allows the arylation of the phthalimide heterocycle under mild and normal practical conditions with good yields. The reaction activities of bromo and chloro bismuthines are however less (Table 6, entries 6 and 7), when substituted with electron withdrawing group, particularly methoxy, reacts well with phthalimide giving 95% yield of 5e (Table 6, entry 5). Electron donating group at para-position favour the formation of cross coupled product over ortho and meta substitution (Table 6, entries 2, 3 and 4) affording excellent yields. In the case of ortho-tolylbismuthine, the influence of sterically hindered methyl substituent on aryl group gives diacetate during reaction course which was clearly seen by its moderate yield (Table 6, entry 2).
Entry | Triaryl bismuthane (2) R | N-Arylated product (5) | Yieldb (%) |
---|---|---|---|
a Conditions: phthalimide (1.0 mmol), Ar3Bi (1.2 mmol), Cu(OAc)2 (1.5 mmol), Cs2CO3 (2.0 mmol), THF (5 mL), 80 °C, 12 h.b Isolated yields. | |||
1 | H (2a) | 5a | 93 |
2 | o-Me (2b) | 5b | 65 |
3 | m-Me (2c) | 5c | 70 |
4 | p-Me (2d) | 5d | 87 |
5 | p-OMe (2e) | 5e | 95 |
6 | p-Br (2f) | 5f | 65 |
7 | p-Cl (2g) | 5g | 45 |
It is important to note that, present protocol tolerate thermally sensitive functional groups in the substrate along with high levels of chemo selectivity, avoiding the occurrence of other competitive coupling reactions such as O-arylation and aryl amidation.
In the step I catalyst activation takes place in the presence of aromatic amine and generates copper diacetate amine complex (a). This complex in step II undergoes oxidative addition with trivalent organobismuth reagent Ar3Bi (b) which leads to the formation of CuI complex (c) and pentavalent organobismuth diacetate Ar3Bi(OAc)2 (d) as key intermediate. In step III ligand coupling takes place between (c) and (d) where phenyl copper(III) species (e) get formed. This species in step IV phenylate amine to afford N-arylated product (f) and CuI X and catalytic cycle was continued.
Oxygen is a highly atom-economical, environmentally benign, and abundant oxidant, which makes it ideal in many ways.31 The chemistry of copper in combination with molecular oxygen, increases exponentially since oxygen can act as either a sink for electrons (oxidase activity) or a source of oxygen atoms that are incorporated into the product (oxygenase activity) or both.32 The oxidation of copper with oxygen is a facile process allowing catalytic turnover in net oxidative processes and ready access to the higher CuIII oxidation state, which facilitates a variety of transformations including two-electron reductive elimination to CuI. Molecular oxygen does not generate toxic byproducts, which get either reduced to water, occasionally via H2O2 or get incorporated into the target structure. Such oxidations using oxygen or air (21% oxygen) have been employed safely in numerous commodity chemical continuous and batch processes.32
As discussed previously an inert atmosphere was not essential, when the reaction was carried out in the pure O2 atmosphere or in a two neck round bottom flask of 50 mL capacity, lower yields of desired product was noticed (Table 4, entries 2 and 7). These results hints that molecular oxygen plays a critical role in a copper catalyzed reaction and suggest the catalytically active species to be Cu(I), which was formed in situ by oxidizing triarylbismuthine with O2 from air during the reaction. The formation of Cu(I) species was supported by the observation of characteristic pale green colour of solution. A sequential color changes observed during the N-arylation reaction indicate that the oxidation of organobismuth(III) compound with subsequent Cu(II) to Cu(I) should be a complex process. The presence of a suitable amount of air in the round bottom flask is crucial to the formation of Bi(V) intermediate. An excess amount of air (or oxygen) is unfavorable to the reaction since the Cu(I) species was further oxidized to less active Cu(II) species, as evidenced by the distinctive blue colored copper amine complex.
It is important to note here that, we were able to isolate in situ formed intermediate (d) under our reaction condition and characterized it as Ar3Bi(OAc)2 by 1HNMR and IR spectroscopy. This signifies the conversion of +3 oxidation state of bismuth to +5 state under copper catalyst in inert solvent. As byproduct during catalytic cycle were presumably H2O2 and CH3COOH which exerts oxidizing action and get enhanced in the presence of added inorganic bases. This might be the reason for in situ oxidation triphenylbismuthine to Ar3Bi(OAc)2.
There are reports where tris(2-methoxyphenyl)bismuth is oxidized to the corresponding diacetate in relatively good yields by iodobenzene diacetate under neutral conditions.33 Oxidation of the trivalent bismuth compound was done by reaction with sodium perborate in acetic acid,34 which led to the diacetate in 63% yield. On the other hand copper diacetate increases the rate of decomposition of triarylbismuth diacetate.35
It is interesting to note that, addition of catalytic amount of copper to intermediate (d) allows high yield and selective phenylation of phthalimide thereby suggesting the role of copper catalyst in N-phenylation. Attempts to isolate bismuth containing byproducts were unsuccessful due to their labile nature but small amount of biaryl were detected together with N-arylated product due to reactivity of triarylbismuthines. The presence of aryl radical species in the course of N-arylation reaction with triarylbismuthane and in situ generated pentavalent organobismuthane [Ar3Bi(OAc)2] was over ruled which is in agreement with the Barton's procedure.
In N-arylation of a different group of N–H containing compounds with triarylbismuth and cupric acetate, tertiary amine such as triethylamine or pyridine act as promoter.36 They play important role in increasing the solubility of the substrate thereby allowing the reaction to proceed at low temperature and in good yields. We are employing Cs2CO3 as optimized base in presence of air atmosphere it also shows enhancement in the solubility of substrate thereby follows similar function as promoter. A base promoter has a remarkable effect in these arylation reactions where product formation in its absence in the case of imidazole is indicative (Table 2, entry 9) and thereby significantly improves the yield in the phenylation of 4-nitroaniline.
In the present study, key mechanistic features of N-arylation reaction were elucidated such as the identity of the catalyst inactive state and isolation of intermediate. In addition principles that motivate the ability of copper that tends to undergo one-electron redox changes, to mediate a two-electron oxidative coupling reaction with a four-electron oxidant (O2) was identified.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra00395h |
This journal is © The Royal Society of Chemistry 2016 |