Mn- and Co-Catalyzed Aminocyclizations of Unsaturated Hydrazones Providing a Broad Range of Functionalized Pyrazolines.

Manganese- and cobalt-catalyzed aminocyclization reactions of unsaturated hydrazones are reported. Whereas manganese catalysis provides access to pyrazoline and tetrahydropyridazine alcohols, cobalt catalysis for the first time paves the way for the selective formation of pyrazoline aldehydes. Furthermore, various functional groups including hydroperoxide, thiol derivatives, iodide, and bicyclopentane may be introduced via manganese-catalyzed ring-forming aminofunctionalization. A progesterone receptor antagonist was prepared using the aminocyclization protocol.

Azoles such as pyrazoles are important building blocks in modern pharmaceutical and agrochemical industry.[1−6] Partially saturated counterparts, in particular 2-pyrazolines, are gaining recognition as promising scaffolds,[7,9] as they offer great opportunity for structural diversification, which has proven to be key in modern drug development.[17,18] In parallel, there has been great interest in building blocks that provide possibilities for design beyond the two-dimensional space of traditional (hetero)aromatic rings.[17,18] Accordingly, leads incorporating 2-pyrazolines have appeared in drug discovery programs for treatment of a wide range of diseases, including cancer,[10,12] diabetes,[15] and malaria.[13] They have also shown anti-inflammatory,[11] -microbial,[13] and -fungal activity (Scheme A).[14] Hence, approaches that lead to this scaffold with diverse functional groups are especially valuable. Herein we report selective manganese- and cobalt-catalyzed aminocyclization reactions of unsaturated hydrazones I that provide a wide variety of functionalized pyrazolines, including aldehydes, alcohols, peroxide, thiol derivatives, iodide, and bicyclopentane (II–VIII, Scheme B).

Scheme 1

Biologically Active Pyrazolines and Cyclization Reactions of Unsaturated Hydrazones

Pyrazolines have commonly been prepared via 1,3-dipolar cycloadditions[19,21] or condensation reactions of enones and hydrazines.[20,25,26] Recently, Cu-catalyzed oxidative cyclization of unsaturated hydrazones has been reported to give pyrazolines.[27] However, this process affords a mixture of aldehydes II (20%), alcohols III (18%), and hydroperoxides IV (40%), thus requiring a subsequent reductive step to convert the mixture into alcohol products. There have also been reports on the use of acridinium[28] and ruthenium[29] photocatalysis to furnish pyrazolines, such as III and V.[30−37] Collectively, these approaches demonstrate the general interest in methods for the preparation of functionalized pyrazolines. However, convenient access is desirable not only to alcohols but also to an expanded set of products that include other groups. These would be especially useful because they may serve as linchpins for further synthetic elaboration. In this respect, selective and efficient access to aldehydes, such as II in Scheme B, has not been reported, despite the fact that they act as a gateway to other functionalities, such as carboxylic acids, amides, nitriles, amines, and heterocycles. Chemler reported the aerobic copper-catalyzed cyclization of 4-pentenylsulfonamides to yield 2-formylpyrrolidines, which were then subjected to oxidative C–C bond cleavage and further transformed into 2-pyrrolidinones.[38,39]

Catalysis by first-row transition metals has gained significant attention because of their low cost and natural abundance.[43] The use of manganese and cobalt catalysis remains relatively underexplored for olefin functionalizations in comparison with other transition metals such as copper, palladium, and nickel,[45−47] yet it offers great opportunities. We have been inspired by one of the earliest examples of preparatively useful cobalt-catalyzed olefin functionalization, namely, the Mukaiyama hydration,[48,49] and related processes.[53,56]

Our prospecting studies commenced by examination of hydrazone 1a as a prototype in a variety of cyclization reactions (Table ). Extensive optimization studies[58] revealed that treatment of 1a with Mn(acac)3 (10 mol %) under an oxygen atmosphere (1 atm) in isopropanol (0.1 M) at 55 °C for 2 h afforded pyrazoline alcohol 2a in 31% yield alongside the corresponding aldehyde 3a in 15% yield (Table , entry 1).[59] Switching to Mn(dpm)3 (dpm = dipivaloylmethanato) significantly improved the reaction outcome and selectivity, providing 2a in 79% yield and 3a in merely 1.6% yield (2a:3a ratio = 98:2) (entry 2). The use of air via a gas inlet instead of a pure oxygen atmosphere furnished alcohol 2a in 68% yield (entry 3). This result was satisfying, as especially on larger scales the handling of molecular oxygen can be hazardous.[60] Lowering the reaction temperature to 25 °C was also feasible with an elongated reaction time (12 h, 65% yield; entry 4). In examining other catalysts (see the Supporting Information), we observed that cobalt salen 4 resulted in a change in the reaction outcome, affording aldehyde 3a in 70% yield, whereas manganese salen 5 did not lead to product formation (entries 5 and 6) .[58,61]

Table 1

Selected Optimization Results for the Mn- and Co-Catalyzed Cyclizations

Determined by 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as the internal standard.

Isolated yield.

Air was continuously introduced into the reaction mixture.

The reaction was conducted at 25 °C for 12 h.

The reaction was conducted at 25 °C for 1 h.

With the optimized reaction parameters in hand for cyclization and selective formation of alcohols, the scope of the reaction was investigated (Scheme ). Various β,γ-unsaturated aryl- and heteroarylhydrazones were submitted to the established reaction conditions, and N-heterocycles 2a–i were obtained in 58–80% yield. Esters and nitriles were well-tolerated in the cyclization reaction, and no difference in reactivity was observed for substrates incorporating electron-donating and -withdrawing substituents. The use of alkylhydrazones as substrates led to the formation of pyrazolines 2j–l in 42–64% yield. In the presence of additional olefins, which could participate in competitive cyclizations, only 5-exo-trig cyclization was observed, and N-heterocycles 2l and 2m were isolated in 42% and 57% yield, respectively. Substrates with substituents on the alkyl chain (1g, 1n, and 1o) were also employed and provided, after cyclization, pyrazolines 2g, 2n, and 2o in 64–79% yield. Replacing the N-tosyl group with N-nosyl (p-nitrophenylsulfonyl) or N-mesyl (methylsulfonyl) was also possible, giving rise to pyrazolines 2i and 2p–r in 70–80% yield. When γ,δ-unsaturated hydrazones were submitted to the reaction conditions, tetrahydropyridazines 2s–v were obtained in 39–73% yield.

Scheme 2

Mn-Catalyzed Cyclizations

The reaction was conducted on a 4 mmol scale.

We then investigated substrates in which the alkene partner was embedded within a ring, which would lead to ring-fused or spiro-pyrazolines (Scheme ). Hydrazones 5a–c as starting materials provided valuable 5,6-fused bicyclic rings 6a–c possessing an anti relative configuration (64–77% yield, dr 10:1 to >20:1), as determined by 1H NMR, X-ray, and 1D NOE data (Scheme ).[62,63] When cyclopentene- and cyclohexene-substituted hydrazones 7a and 7b were used, [4.4] and [4.5] spirocycles 8a and 8b were prepared in high yields with excellent diastereoselectivity (64% and 75% yield, dr >20:1 and 8:1, respectively; Scheme ).

Scheme 3

Preparation of Fused and Spiro Pyrazolines

Mn(dpm)3 (20 mol %) was used.

During the optimization studies aimed at preparation of the primary alcohol product shown in Table , we observed that the formation of aldehyde 3a was preferred with the use of Co-salen 4 as catalyst (see Table , entry 6). Given the rather limited number of examples of cyclization reactions of olefins that produce aldehydes, we set out to investigate the scope of this transformation (Scheme ). Various functional groups including nitriles and esters were well-tolerated, yielding aldehydes 3a–f in 46–83% yield.[64] Replacing the oxygen atmosphere by air via a gas inlet led to 3a in 57% yield. When furan and thiophene hydrazones were employed, pyrazolines 3g and 3h were isolated in 63% and 53% yield, respectively. Other sulfonamides could be used, such as N-mesyl and N-nosyl, yielding aldehydes 3i and 3j, both in 47% yield (Scheme ). We speculate that the cobalt catalyst mediates cyclization, formation of a terminal hydroperoxide, and its collapse to aldehydes 3a–j.[65]

Scheme 4

Co-Catalyzed Cyclizations

Air was continuously introduced into the reaction mixture.

We then proceeded to examine the use of other reactive traps instead of oxygen (Scheme ). After prospecting experiments, we found a standard set of conditions in which stirring 1a with various reactants in the presence of Mn(dpm)3 (10 mol %) and tBuOOH (2 equiv) in iPrOH under N2 (1 atm) gave a variety of adducts. In the presence of diphenyl disulfide (2 equiv) thioether 9a was formed in 58% yield. The reaction of 1 with S-benzyl O-ethyl carbonodithioate and O-benzyl S-ethyl carbonodithioate afforded xanthate 9b and carbonodithioate 9c in 58% and 84% yield, respectively. With [1.1.1]propellane, bicyclopentane derivative 9d was obtained in 58% yield. The use of allyl iodide afforded primary iodide 9e in 87% yield. Interestingly, in the absence of additional reactants, treatment of 1a with Mn(dpm)3 (10 mol %) and tBuOOH (2 equiv) in iPrOH under N2 (1 atm) provided 9f in 55% yield.[66] When the appropriate unsaturated hydrazone was employed as the starting material it was possible to prepare pyrazoline 9g, a progesterone receptor antagonist,[9] in 53% yield. In cyclizations leading to 9f and 9g, iPrOH acts as a hydrogen donor, as described in the early work of Mukaiyama.[61,67] When the reaction was conducted in DCE instead of iPrOH, tert-butylhydroperoxide quenched the reactive intermediate to give dialkyl peroxide 9h in 87% yield (Scheme ).

Scheme 5

Mn-Catalyzed Aminofunctionalizations

Diphenyl disulfide as the reactant.

S-benzyl O-ethyl carbonodithioate as the reactant.

O-benzyl S-ethyl carbonodithioate as the reactant.

[1.1.1]propellane as the reactant.

allyl iodide as the reactant.

No reactant.

Mn(dpm)3 (30 mol %) was used.

No reactant; DCE was used as the solvent.

Finally, various synthetic transformations were performed using pyrazoline and tetrahydropyridazine alcohols (Scheme ).[62] Reaction of 2a with Bu4NF led to elimination of the N-tosyl group, which provided pyrazole 14 in 75% yield. When N-nosyl pyrazoline 2p was treated with thiophenol at room temperature in the presence of K2CO3 followed by benzyl bromide, pyrazoline 15 was obtained in 56% yield.[68] It was also possible to prepare the corresponding hydrochloride salt 16 in 46% yield by addition of 2 M HCl in dioxane after sulfonamide cleavage.[69] Removal of the N-nosyl group from tetrahydropyridazine 2v could also be carried out, affording azine 17 in 65% yield (Scheme ).

Scheme 6

Derivatization of the Pyrazolines and Tetrahydropyridazine

In summary, we have disclosed manganese- and cobalt-catalyzed cyclization reactions of unsaturated hydrazones that gave divergent access to a range of complex and highly functionalized N-heterocycles. Whereas aerobic manganese catalysis led to the formation of pyrazoline and tetrahydropyridazine alcohols, a cobalt–salen catalyst for the first time allowed the preparation of pyrazoline aldehydes. Addition of various reactants to the cyclization reaction paved the way for the formation of a variety of functionalized pyrazolines as well as a progesterone receptor antagonist. Finally, synthetic transformations of the prepared products were performed, demonstrating the utility of the cyclization protocol. We are in the process of further developing cyclization reactions that lead to versatile aldehyde products, and the results will be reported as they become available.