Wei Wuab,
Xin-Heng Fan*a,
Li-Peng Zhangab and
Lian-Ming Yang*a
aBeijing National Laboratory for Molecular Sciences (BNLMS), Key laboratory of Green Printing, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P.R. China. E-mail: yanglm@iccas.ac.cn; Fax: +86-10-62559373; Tel: +86-10-62565609
bGraduate School of Chinese Academy of Sciences, Beijing 100049, P.R. China
First published on 3rd December 2013
A nickel-catalyzed method for the cross-coupling of benzophenone hydrazone with aryl bromides is described. The use of a simple Ni(II)/NHC catalyst leads to the arylated hydrazones in good or acceptable yields. This protocol provides a simple, convenient alternative to the synthesis of arylhydrazines.
Benzophenone hydrazone is one of the most commonly employed hydrazine surrogates because it is readily available and conveniently used, and the resulting N-arylated benzophenone hydrazone are easily deprotected to afford the corresponding free arylhydrazines. Initially, the cross-coupling between p-bromotoluene (1a) and benzophenone hydrazone was selected as a model reaction to screen the optimal reaction conditions (Table 1). Since our previous work14 has proven that a combination of [Ni]/N-heterocyclic carbene (NHC) was often an catalyst system more suitable for nickel-catalyzed aromatic aminations, the two model substrates was first subjected to the conditions of Ni(PPh3)2Cl2/IPr·HCl/t-BuONa at room temperature in dioxane. Encouragingly, the coupling reaction was found to proceed with 54% yield of the product 2a (entry 1). Furthermore, one advantage of the reaction is that a simple NiII complex rather than the hard-to-handle Ni0 source (highly sensitive to air/moisture and toxic) was employed as precatalyst. In contrast, this cross-coupling did not occur in the absence of the nickel catalytic system whether at room temperature or elevated temperatures (entry 2), where only a decomposition of benzophenone hydrazone was observed. Our experiments showed that benzophenone hydrazone partially decomposes into free hydrazine and benzophenone under the basic conditions, and the decomposition exacerbates with elevating reaction temperatures (entry 2). Obviously, this decomposition side-reaction would hamper the achievement of the desired product in excellent yields because it competes against the desired coupling reaction. Further experimentation determined a balance point of reaction temperatures between maximizing the desired coupling reaction and minimizing the decomposition side-reaction, achieving a good yield of 73% (entry 3). A survey of other common nickel sources suggested that all the NiII precursors have a certain degree of efficacy in this transformation, affording the desired product in 50–60% yields (entries 4–7). The nature of the bases used is crucial for this reaction. For example, strong base t-BuOK (entry 8) led to a substantial decomposition of benzophenone hydrazone and a complicated outcome; weaker bases such as Cs2CO3 (entry 9) and K3PO4 (entry 10) as well as a special base NaH (entry 11) did not work at all. As shown, the catalytic activity of the Ni catalyst was highly relevant to ancillary ligands since other types of ligands (entries 12–14) and even SIPr·HCl (entry 15) (a saturated counterpart of IPr·HCl) proved to be ineffective. For the solvents used, THF (entry 16) was far inferior but toluene (entry 17) comparable to dioxane. Additionally, our experiments showed that p-chlorotouene was intact and p-iodotoluene afforded a only slightly better yield (75%) under the optimized reaction conditions as established in entry 3 of Table 1.
Entry | [Ni] | Ligand | Base | Solvent | Yieldb (%) |
---|---|---|---|---|---|
a Reaction conditions: p-bromotoluene (1.0 mmol), the hydrazone (1.3 mmol), [Ni] (0.05 mmol), ligand (0.1 mmol), base (1.3 mmol), solvent (2.5 mL), 50 °C, 5 h.b Isolated yield.c IPr·HCl: 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride.d A room-temperature reaction.e Reactions conducted at rt, 60 °C, and 100 °C, respectively.f C1: Ni(PPh3)2(1-naphthyl)Cl.g C2: Ni(PPh3)2(phenyl)Br.h Complicated products not determined.i No reaction.j PCy3: tricyclohexylphosphine.k DPPF: 1,1′-bis(diphenylphosphino)ferrocene (0.05 mmol).l Phena: 1,10-phenanthroline (0.05 mmol).m SIPr·HCl: 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium chloride (0.1 mmol). | |||||
1 | Ni(PPh3)2Cl2 | IPr·HClc | t-BuONa | Dioxane | 54d |
2 | None | None | t-BuONa | Dioxane | 0e |
3 | Ni(PPh3)2Cl2 | IPr·HCl | t-BuONa | Dioxane | 73 |
4 | Ni(acac)2 | IPr·HCl | t-BuONa | Dioxane | 57 |
5 | NiCl2·6H2O | IPr·HCl | t-BuONa | Dioxane | 52 |
6 | C1f | IPr·HCl | t-BuONa | Dioxane | 59 |
7 | C2g | IPr·HCl | t-BuONa | Dioxane | 58 |
8 | Ni(PPh3)2Cl2 | IPr·HCl | t-BuOK | Dioxane | NDh |
9 | Ni(PPh3)2Cl2 | IPr·HCl | CsCO3 | Dioxane | NRi |
10 | Ni(PPh3)2Cl2 | IPr·HCl | K3PO4 | Dioxane | NR |
11 | Ni(PPh3)2Cl2 | IPr·HCl | NaH | Dioxane | NR |
12 | Ni(PPh3)2Cl2 | PCy3j | t-BuONa | Dioxane | 0 |
13 | Ni(PPh3)2Cl2 | DPPFk | t-BuONa | Dioxane | 0 |
14 | Ni(PPh3)2Cl2 | Phenal | t-BuONa | Dioxane | 0 |
15 | Ni(PPh3)2Cl2 | SIPr·HClm | t-BuONa | Dioxane | 0 |
16 | Ni(PPh3)2Cl2 | IPr·HCl | t-BuONa | THF | 23 |
17 | Ni(PPh3)2Cl2 | IPr·HCl | t-BuONa | Toluene | 70 |
Several commonly-used hydrazine equivalents were also tested in the N-arylation reaction (Scheme 1). Consequently, it was found that these other hydrazine surrogates did not undergo the cross-coupling with p-bromotoluene under our optimal conditions. The outcomes cannot yet be clearly explained at present and further studies are needed.
Next, we examined N-arylation of benzophenone hydrazone with some representative bromoarenes under the optimized conditions (Table 2). Generally, the coupling reaction indeed took place with various aryl bromides but the yields were not very high in many cases. This may be likely because the complicated side-reactions always, to more or less degree, exist in the present reaction system. Taking unsubstituted, electron-neutral bromobenzene (2d) as the standard, the electronic nature of the substituents on aryl bromides does not seem to produce significant influence on the reaction (2a, 2e, 2i, 2j, and 2m). And quite different from usual metal-catalyzed coupling reactions, the adverse influence of electron-donating groups on the electrophilic partner is less than that of the electron-withdrawing ones (2a, 2e, and 2m vs. 2i and 2j). The reason is unclear at this time. On the other hand, the reaction is extremely sensitive to the steric effects of aryl bromides. Even when the substituents are at the meta position of bromoarenes, the yields diminished apparently (2b, 2f, 2k, and 2o); the ortho-substituted aryl bromides (more sterically demanded) gave much lower yields of the coupled products (2c, 2g, 2h, and 2n) with appreciable amounts of the starting material 1 recovered, and the elevated reaction temperature scarcely help the increase of yields (2c, 2g, and 2h). p-Dibromobenzene was smoothly mono-arylated in a moderate yield (2l), and heteroaryl bromide was also coupled with benzophenone hydrazone depite that the yield was not high (2p). It must be pointed out that the current conditions are intolerant of some functional groups such as cyano and ester, which were found to react with the free amino group of benzophenone hydrazone, and thus both bromo-benzonitrile and benzoate are not suitable substrates for the reaction.
a Conditions: bromoarene (1.0 mmol), hydrazone (1.3 mmol), Ni (0.05 mmol), IPr·HCl (0.1 mmol) t-BuONa (1.3 mmol), dioxane (2.5 mL), 50 °C, 5 h; isolated yield.b The reaction conducted at 100 °C. | |||
---|---|---|---|
![]() |
![]() |
![]() |
![]() |
2a 73% | 2b 58% | 2c 44% (46%b) | 2d 74% |
![]() |
![]() |
![]() |
![]() |
2e 70% | 2f 59% | 2g 22%b | 2h 20%b |
![]() |
![]() |
![]() |
![]() |
2i 65% | 2j 60% | 2k 43% | 2l 50% |
![]() |
![]() |
![]() |
![]() |
2m 66% | 2n 41% | 2o 50% | 2p 35% |
Aryl benzophenone hydrazones 2 may be regarded as a form of protected arylhydrazines and can be readily converted into the corresponding arylhydrazines by acidic hydrolysis. In the cases shown in Scheme 2, the hydrazone 2 was completely deprotected at room temperature in a mixture of concentrated hydrochloric acid and methanol (10:
1 v/v), affording an arylhydrazine hydrochloride 3 simply by filtration and washing with CH2Cl2. Note that achieving only modest isolated yields results mainly from easy loss of the salt 3 in the purification process.
In the practical use, often it is not necessary to hydrolyzed aryl benzophenone hydrazones and isolate arylhydrazines beforehand. For example, a useful class of intermediate compounds 4 in the synthesis of N,N-diarylhydrazines15 can be prepared easily from the exchanging reaction of aryl benzophenone hydrazones 2 with 2-pyridinealdehyde in excellent yields (Scheme 3); when the hydrazone 2 is treated with an enolizable ketone,6c the indole product 5 can be provided by the Fischer reaction in a one-pot mode (Scheme 4).
In conclusion, we have first demonstrated the feasibility for nickel-catalyzed cross-couplings of hydrazine-type substrates with haloarenes. Aryl benzophenone hydrazones can be prepared via nickel-catalyzed N-arylation of benzophenone hydrazone with bromoarenes under relatively mild conditions. This protocol provides a simple, convenient, and inexpensive route to arylhydrazines. Studies to improve the efficiency of Ni-based catalyst systems, expand the scope of electrophilic coupling partners, and understand the mechanistic details of reaction are under way, and the results will be reported in due course.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra46288a |
This journal is © The Royal Society of Chemistry 2014 |