Parul Chauhan‡
a,
Makthala Ravi‡a,
Shikha Singha,
Kanumuri S. R. Rajuc,
Vikas Bajpaib,
Brijesh Kumarb,
Wahajuddinc and
Prem. P. Yadav*a
aDivision of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow-226031, India. E-mail: pp_yadav@cdri.res.in; ppy_cdri@yahoo.co.in; Fax: +91-522-2623405/2623938; Tel: +91-522-2612411-18 ext. 4761/4762
bSophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow-226031, India
cDivision of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Lucknow-226031, India
First published on 5th September 2014
An efficient protocol has been developed for the synthesis of biaryls via Pd/Cu catalyzed coupling of phenylhydrazines in water. Homo and cross couplings were successfully achieved in a ligand-free catalytic system, at room temperature with water as sole reaction medium.
We started the reaction of 1a in the presence of palladium acetate (5 mol%) and copper acetate (10 mol%) in water for 20 min at r.t. To our delight, the reaction proceeded smoothly and provided biaryl 2a in 80% yield (Table 1, entry 1). To the best of our knowledge, this is the first report on Pd catalyzed synthesis of biaryls from phenylhydrazines using Cu as an oxidant in water.
Entry | Pd source | X | Y | Solvent | Time | Yieldb (%) |
---|---|---|---|---|---|---|
a Reaction condition: 1a (0.62 mmol), catalyst (X mol%), Cu(OAc)2 (Y mol%), solvent (10 mL) at rt.b Isolated yields.c Equivalents. | ||||||
1 | Pd(OAc)2 | 5 | 10 | H2O | 20 min | 80 |
2 | Pd(TFA)2 | 2.5 | 10 | H2O | 15 min | 90 |
3 | Pd(TFA)2 | 5 | 10 | H2O | 15 min | 90 |
4 | PdCl2 | 5 | 10 | H2O | 1 h | 75 |
5 | Pd(PPh3)2Cl2 | 5 | 10 | H2O | 2 h | 65 |
6 | Pd(PPh3)4 | 5 | 10 | H2O | 3.5 h | 41 |
7 | Pd(TFA)2 | 2.5 | 5 | H2O | 2 h | 78 |
8 | Pd(TFA)2 | 2.5 | 20 | H2O | 15 min | 90 |
9 | Pd(TFA)2 | 2.5 | 10 | DMF | 15 min | 90 |
10 | Pd(TFA)2 | 2.5 | 10 | EtOH | 20 min | 80 |
11 | Pd(TFA)2 | 2.5 | 10 | THF | 20 min | 80 |
12 | Pd(TFA)2 | 2.5 | 10 | MeOH | 20 min | 75 |
13 | Pd(TFA)2 | 2.5 | 10 | DMSO | 20 min | 85 |
14 | Pd(TFA)2 | 2.5 | 10 | Toluene | 20 min | 65 |
15 | PdCl2 | 2.5 | 10 | DMF | 1 h | 79 |
16 | Pd(PPh3)2Cl2 | 2.5 | 10 | DMF | 2 h | 67 |
17 | Pd(PPh3)4 | 2.5 | 10 | DMF | 3.5 h | 42 |
18 | Pd(OAc)2 | 2.5 | 10 | DMF | 2 h | 80 |
19 | Pd(TFA)2 | 1c | — | H2O | 15 min | 0 |
20 | — | — | 1c | H2O | 15 min | 0 |
Encouraged by these results, we next evaluated various Pd(II) sources (Table 1, entries 1–6) and found that Pd(TFA)2 (2.5 mol%) is the best Pd source, affording 90% yield of 2a (Table 1, entry 2). Increasing the catalytic loading of palladium from 2.5 mol% to 5 mol% there was no improvement in yield (Table 1, entry 2 versus entry 3). Further a set of reactions were performed to investigate the influence of catalytic amount of copper acetate and found that 10 mol% copper acetate provided best yield (Table 1, entry 2), 5 mol% of copper acetate led to reduction of yield to 78% (Table 1, entry 7) and no further improvement was observed while increasing catalytic loading to 20 mol% (Table 1, entry 8). Other copper sources such as CuCl2 and CuBr2 provided moderate yields (Table 2, entries 1–2), whereas Cu(I) sources such as CuI and Cu2O resulted in abrupt reduction in yields (Table 2, entries 3–4). Non-copper oxidants such as Ag2CO3, TBHP and Iodine were also screened (Table 2, entries 5–7) and none of them were more efficient than the copper acetate for this conversion. Other organic solvents (Table 1, entries 9–14) were also screened and found to give moderate to high yield of 2a where reaction in DMF provided almost comparable yield as compared to water (Table 1, entries 9 and 5–18). After having promising results in hand for the model system, the scope of substituted phenylhydrazines was investigated (Table 3). Optimized protocol was applied to a range of mono (Table 3, entries 1–6 and 8) and disubstituted (Table 3, entries 7 and 9) phenylhydrazines to afford good to excellent yield of corresponding biaryls. Reactions of phenylhydrazines having electron withdrawing groups such as fluoro, chloro, bromo, cyano, nitro and dichloro (Table 3, entries 1a–1c and 1e–1g) and electron donating groups such as methoxy and dimethyl (Table 3, entries 8 and 9) proceeded with similar efficiency and afforded 2a–2i in 68–90% yields (Table 3, entries 1–9).
Entry | Co-catalyst | Time | Yieldb |
---|---|---|---|
a Reaction condition: 1a (0.62 mmol), Pd(TFA)2 (2.5 mol%), co-catalyst (10 mol%), water (10 mL) at rt.b Isolated yields.c TBHP (1 equivalent).d TBHP (1 equivalent) + CuI (10 mol%). | |||
1 | CuCl2 | 30 min | 68 |
2 | CuBr2 | 30 min | 85 |
3 | CuI | 1 h | 35 |
4 | Cu2O | 2 h | None |
5 | Ag2CO3 | 30 min | 60 |
6 | TBHPc | 1 h | 55 |
7 | Iodine | 30 min | 51 |
8 | TBHP + CuId | 20 min | 85 |
Entry | R | Product | Time | Yieldb (%) |
---|---|---|---|---|
a Reaction condition: 1a (0.62 mmol), Pd(TFA)2 (2.5 mol%), oxidant (10 mol%), water (10 mL) at rt.b Isolated yields. | ||||
1 | 4-F | ![]() |
15 min | 90 |
2 | 4-Br | ![]() |
20 min | 85 |
3 | 4-Cl | ![]() |
15 min | 90 |
4 | H | ![]() |
20 min | 82 |
5 | 4-CN | ![]() |
1 h | 69 |
6 | 4-NO2 | ![]() |
30 min | 81 |
7 | 3,4-Di-Cl | ![]() |
25 min | 79 |
8 | 4-OMe | ![]() |
2 h | 68 |
9 | 3,4-Di-Me | ![]() |
1 h | 80 |
Notably, halogen groups were compatible with this reaction (2a–2c). Most of the C–C coupling strategies use aryl halides as aryl source, whereas in our process halides are retained in the coupled product. Further cyano and nitro groups are also compatible with present methodology. These functional groups are important post coupling diversification points in medicinal chemistry.14
The present method also afforded unique 4,4′-biquinoline efficiently and may prove to be a key process for synthesis of biologically active biheterocycles (Scheme 2).15
We tested our methodology for cross coupling reactions of chloro, bromo, fluoro and cyano substituted phenylhydrazines with methoxy and cyano substituted phenylhydrazine under optimized reaction condition (Table 1, entry 2). Cross coupling proceeded smoothly and afforded desired unsymmetrical biaryls (3) in 41–76% yields (Table 4, entries 1–6).
Entry | R | R1 | Cross coupling product (3) | Time | Yieldb(%) (3, 2, 2′) |
---|---|---|---|---|---|
a Reaction condition: 1 (0.57 mmol), 1′ (0.68 mmol), Pd(TFA)2, (2.5 mol%), Cu(OAc)2 (10 mol%), water (10 mL) at rt.b HPLC yields. | |||||
1 | Cl | OMe | ![]() |
2 h | 76, 2, 21 |
2 | Br | OMe | ![]() |
2.5 h | 75, 6, 19 |
3 | F | OMe | ![]() |
2 h | 71, 13, 15 |
4 | CN | OMe | ![]() |
3.5 h | 41, 55, 3 |
5 | Cl | CN | ![]() |
2.5 h | 59, 11, 30 |
6 | Br | CN | ![]() |
2.5 h | 64, 25, 10 |
The methodology was further extended for synthesis of anticancer pharmacophore 2-arylbenzothiazole16 (Scheme 3) and Suzuki coupling of aryl boronic acids with phenylhydrazines (Scheme 4).
Recently, Zhao et al., reported Pd-catalyzed Suzuki coupling of phenylhydrazines with arylboronic acid using phosphine ligands, acids and NMP as solvent at 90 °C.17 Peng et al., also reported Pd-catalyzed Suzuki coupling of phenylhydrazines with arylboronic acid while using TsCl for activation of hydrazine, SDS as PTC in water at 60 °C.18 We herein executed Suzuki cross-coupling of 4-methoxyphenylboronic acid with 4-chlorophenylhydrazine (Scheme 4) under our optimized conditions in water at room temperature without using any hydrazine activation agents like TsCl, ligand and PTC. Further optimization of yield is under progress.
We next conducted some experiments to investigate the role of metals in this reaction. When phenylhydrazine 1a was reacted under optimized conditions with Pd(TFA)2 in absence of Cu(II), no product was observed (Table 1, entry 19). Similarly reaction without Pd(TFA)2 but with Cu(OAc)2 under optimized condition did not afford any biaryl product indicating that both of these metals are essential for coupling (Table 1, entry 20). Also TEMPO displayed a negligible effect on the reaction of 1a in the presence of Pd/Cu to afford 2a, ruling out a radical pathway.
Although a detailed study is required to fully understand the exact mechanism of homo and cross coupling of phenylhydrazines and role of Cu in catalytic cycle, a tentative pathway can be proposed on the basis of our observations and previous reports on phenylhydrazine couplings8,13a (Fig. 1). Phenylhydrazine A undergoes oxidation in the presence of Cu(II) to form diazene intermediate B or complex C, which subsequently undergoes transmetalation with Pd(II) followed by expulsion of N2 to afford intermediate E. A second transmetalation of intermediate E with C or B to produce a bis-aryl palladium(II) species F, which subsequently undergoes reductive elimination to afford the desired homo and cross-coupled product G and Pd(0). Finally Pd(0) undergo oxidation to Pd(II) completing the catalytic cycle.
Footnotes |
† Electronic supplementary information (ESI) available: Experimental procedures, data and NMR spectra of all the final compounds. See DOI: 10.1039/c4ra04621h |
‡ P.C and M.R. contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2014 |