Trifluoromethylated Pyrazoles via Sequential (3 + 2)-Cycloaddition of Fluorinated Nitrile Imines with Chalcones and Solvent-Dependent Deacylative Oxidation Reactions.

A general approach for preparation of two types of polyfunctionalized 3-trifluoromethylpyrazoles is reported. The protocol comprises (3 + 2)-cycloaddition of the in situ generated trifluoroacetonitrile imines with enones leading to trans-configured 5-acyl-pyrazolines in a fully regio- and diastereoselective manner. Initially formed cycloadducts were aromatized by treatment with manganese dioxide. Depending on the solvent used, the oxidation step either led to fully substituted pyrazoles (DMSO) or proceeded via a deacylative pathway to afford 1,3,4-trisubstituted derivatives (hexane) with excellent selectivity.

In the past two decades, great attention has been focused toward the chemistry of pyrazoles functionalized by introduction into the heterocyclic ring of either fluorine atom(-s) or fluoroalkylated groups.[1] In a series of recent publications they were reported as organic materials of remarkable practical importance, and specifically 3-trifluoromethylated pyrazole has been indicated as a privileged structural scaffold for a variety of agrochemicals, pharmaceuticals, and advanced materials.[1,2] For these reasons, development of new methods aimed at efficient and selective synthesis of multifunctionalized, fluorinated pyrazoles is a challenging problem in current organic synthesis.

In general, common access to 3-trifluoromethylpyrazoles relies on condensation of corresponding 1,3-dicarbonyl compounds (or their equivalents) with a functionalized hydrazines.[1−3] In addition, Lewis acid mediated cyclizations and related transformations of hydrazones are also applied.[4] Furthermore, some postcyclization, functional group interconversions leading to trifluoromethylated pyrazoles, and catalytic fluoroalkylations have been developed more recently.[5] Another powerful approach is based on 1,3-dipolar cycloadditions employing trifluoromethylated 1,3-dipoles and appropriate dipolarophiles. In the past decade, remarkable progress has been achieved in the chemistry of 2,2,2-trifluorodiazoethane; however, some drawbacks such as difficult handling, low selectivity, and the scope limited to pyrazoles lacking a substituent at N(1) have been pointed out.[6] In contrast, applications of alternative 1,3-dipolar intermediates, i.e. trifluoroacetonitrile imines 1, offer access to N-functionalized heterocycles, and typically, their reactions proceed with excellent regio- and chemoselectivity.[7] Nevertheless, application of easily accessible nitrile imines 1 for preparation of the title 3-trifluoromethylated pyrazoles remain underexplored.

Some time ago, Oh (but also our group) demonstrated that by using electron-rich C=C dipolarophiles such as enamines or vinyl ethers,[8] the problem of low regioselectivity, reported by Tanaka in his pioneering work on 1,3-dipolar cycloadditions of 1 with nonactivated alkenes, could easily be overcome.[9] As shown in Scheme , the presence of −NR2 or −OR as a leaving group in an ethylenic dipolarophile assures complete regioselectivity in the (3 + 2)-cycloaddition step and the initially formed products undergo either spontaneous or Brönsted acid induced elimination of an amine or alcohol molecule, respectively, to give the final aromatized heterocycle. More recently, Ma and co-workers developed an interesting one-pot decarboxylative (3 + 2)-cycloaddition route leading to fully substituted CF3-pyrazoles, starting with nitrile imines and isoxazolidinediones as dipolarophiles.[10] In that case, thermal extrusion of CO2 from the corresponding intermediate was pointed out as a driving force leading to the final, aromatized product. Remarkably, neither of the methods developed thus far explores the orthogonal properties of the initially formed (3 + 2)-cycloadducts. Thus, in the search for new synthetic protocols toward polyfunctionalized 3-trifluoromethylpyrazoles, we envisioned possible access to three- and tetra-substituted analogues by using 5-acylpyrazolines as common precursors. The requisite starting materials can be obtained by employing azomethine imines as reported by Xie,[11] but they should also be accessible via anticipated regioselective (3 + 2)-cycloaddition of acyclic enones with in situ generated fluorinated nitrile imines 1 (Scheme ). Here we report on the efficient synthesis of two distinct classes of polysubstituted 3-trifluoromethylpyrazoles via a two-step protocol comprising (i) diastereoselective (3 + 2)-cycloaddition of 1 with chalcones followed by (ii) solvent-controlled, competitive oxidation vs deacylative aromatization of the intermediate pyrazolines by using MnO2 as a convenient oxidant.

Scheme 1

General Schemes of (a) Generation of Nitrile Imines 1, (b) Their Reactions with Electron-Rich Alkenes, (c) and the Solvent-Controlled Synthesis of Polysubstituted 3-Trifluoromethylpyrazoles Reported Herein

The model 5-benzoylpyrazoline 2a was prepared by the reaction of chalcone 4a with an excess of hydrazonoyl bromide 3a in the presence of Et3N as a base, at room temperature (Scheme ).[7b] Gratifyingly, the expected trans-configured pyrazoline 2a was formed as the only product under the applied conditions. In the search for an efficient oxidizing reagent, we directed attention to MnO2 as a common oxidant which has broadly been applied, e.g. in diverse dehydrohalogenation processes.[12,13] More importantly, despite its well-known mildness under neutral conditions, successful oxidation of some carbonyl compounds into respective carboxylic acids is also known.[14] The first experiment was aimed at oxidation of model pyrazoline 2a with excess MnO2 (ca. 85%, <10 μm), which was carried out in DCM solution, and the formation of a single product 5a in ca. 37% yield was observed after 2 d at room temperature (Table , entry 1). Interestingly, in the 13C NMR (151 MHz, CDCl3) spectrum of 1,4-diphenyl-3-trifluoromethylpyrazole (5a), along with the expected quartets found at δ = 122.7 (1JC–F = 269.9 Hz) and δ = 140.5 (2JC–F = 36.6 Hz) attributed to the CF3 group and the C(3) atom, respectively, the presence of another quartet at δ = 128.8 (JC–F ≈ 1.2 Hz) resulting from through-space coupling between F atoms and the ortho-C atoms of the neighboring Ph ring additionally confirmed the expected substitution pattern in 5a.

Scheme 2

Synthesis of 3-Trifluoromethylpyrazoline 2a

Table 1

Oxidation of 3-Trifluoromethylpyrazoline 2a with MnO2a

			ratio [%]b (isolated yield)
entry	solvent	temp	2a	5a	6a
1	DCM	rt	63	37	–
2	hexane	rt	46	54	–
3	toluene	rt	79	21	–
4	hexane	60 °C	–	96 (94)	4
5	hexanec	60 °C	–	98 (97)	2
6	THF	rt	89	11	–
7	MeCN	rt	90	10	–
8	DMSO	rt	100	–	–
9	MeCN	75 °C	–	53	47
10	DMF	100 °C	–	33	67
11	DMF	130 °C	–	35	65
12	DMSO	100 °C	–	7	93 (79)
13	DMSOc	100 °C	–	10	90 (81)
14	DMSOd	100 °C	–	8	92
15	DMSOe	100 °C	100	–	–

Reaction conditions: a solution of 2a (0.20 mmol) in corresponding solvent (3 mL) and solid MnO2 (20 equiv) were stirred magnetically in a 10 mL flask for 2 d.

Estimated based on 1H NMR spectra of crude mixtures.

1 mmol (2a) scale.

Reaction performed in the presence of atmospheric moisture (open flask).

Heating in absence of MnO2.

Examination of the solvent effects revealed that decreased polarity of the organic medium favors deacylative oxidation leading to pyrazole 5a (54% in hexane, entry 2), whereas only traces or no formation of this product was observed in THF, MeCN, and DMSO solutions.[15] Increasing the temperature of the hexane solution resulted in complete conversion of starting pyrazoline 2a into 5a (96%) which was accompanied only by trace amounts of 5-benzoyl-functionalized pyrazole 6a formed as a side product. On the other hand, oxidation of 2a at elevated temperature in polar media such as MeCN, DMF, and DMSO proceeded partially with preservation of the benzoyl group and led to mixtures of 5a and 6a (entries 9–12). In the latter experiment performed in DMSO, preferential formation of the tetrasubstituted product was observed. Gratifyingly, both oxidation reactions could successfully be scaled up (1.0 mmol) without any remarkable loss of selectivity (entries 5 and 13). Furthermore, the optimized deacylative protocol was found to be operationally very simple; both the benzoic acid formed as the only byproduct and the remaining solid MnO2 could be filtered off to give, after removal of the solvent, spectroscopically pure product 5a. Subsequent filtration of this material through a short silica gel pad provided analytically pure sample. The observed switch of chemoselectivity also deserves a brief comment. Possibly, the reaction carried out in the nonpolar hexane solution is initiated by oxidation at the benzyl-like position C(4) of the trans-configured pyrazoline 2 and proceeds preferentially via deacylative fashion due to close proximity of the benzoyl group and the “activated surface” of MnO2. Apparently, replacement of the nonpolar solvent by polar DMSO reduces the oxidative potential of MnO2,[12] and hence, observed trans elimination of two H-atoms takes place.

With the optimized conditions in hand, we investigated the scope and limitations of the developed solvent-controlled oxidation procedure. Hence, a series of 5-benzoylpyrazolines 2b–2q were prepared in analogy to the model reaction depicted in Scheme in acceptable yields of 44–96%, and next, the obtained products 2 were subjected to reaction with MnO2 (Scheme ; for detailed procedure, see Supporting Information). First, a series of pyrazolines 2b–2h, derived from chalcone 4a and differently substituted nitrile imines 1, were examined in oxidation reactions.

Scheme 3

Oxidation of Pyrazolines 2 with MnO2; Scope of Substrates

If not stated otherwise, the yields refer to isolated yields.

Obtained from pyrazoline 2g.

The formation of 6k (ca. 27% based on 1H NMR of crude mixture) was observed.

The formation of 5k (59%) was observed; yield estimated based on 1H NMR spectrum of crude mixture.

In all the tested examples, the expected products 5 and 6 were formed in high yields and with excellent selectivity, regardless of the electronic (OBn, NO2) and steric (2,4-di-Cl) features of the substituent present in the aryl ring located at N(1). Only in the case of 4-benzoyloxy derivative 2g oxidation in hot DMSO proceeded with complete deprotection of the ester unit to afford phenol 6g as the only product. Next, a second set of pyrazolines (2i–2q) obtained by condensation of differently substituted chalcones 4 with p-tolyl functionalized nitrile imine was examined. Again, excellent selectivity and high yields were noticed for this series except from the ferrocenyl-functionalized analogues 2k and 2q. In the first case, the presence of the redox-active Fc group located at C(4) interfered with complete selectivity of the oxidation to provide ca. 7:3 and ca. 6:4 mixtures of 5k and 6k in hexane and DMSO, respectively. On the other hand, introduction of ferrocenoyl unit at C(5) in pyrazoline 2q favored debenzoylative aromatization to provide pyrazole 5c as a major product in both experiments. The structures of two representative compounds in this series, 2q and 6n, were unambiguously confirmed by X-ray analysis.[16]

In order to demonstrate the essential role of the electron-withdrawing C=O group located at the C(5) in the formation of 1,4-disubstituted 3-trifluoromethylpyrazoles 5, the stilbene-derived trans-pyrazoline 7 was synthesized and applied for the reaction with MnO2 in hexane (Scheme ). In that case, the expected 1,4,5-triphenyl-3-trifluoromethylpyrazole (8, 90%) was obtained as the sole product after 2 d of heating at 60 °C. Next, (E)-4-phenyl-3-buten-2-one and methyl trans-cinnamate were also reacted with nitrile imine 1a to yield the expected pyrazolines 9a and 9b, respectively. Subsequent treatment with MnO2 in hot hexane provided the known pyrazole 5a lacking a substituent at C(5), hence indicating also methoxycarbonyl- and acetyl-functionalized pyrazolines as suitable substrates for the described deacylative aromatization reaction. Furthermore, two more bis-trifluoromethylated pyrazoles 5r and 6r were efficiently prepared via solvent-controlled oxidation starting with pyrazoline 2r obtained via (3 + 2)-cycloaddition of nitrile imine 1c with the known CF3-functionalized enone, namely, with (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one (Scheme ).[17] This result demonstrates again that electron-deficient nitrile imines 1 derived from trifluoroacetonitrile are very prone 1,3-dipoles which are able to react even with strongly electron-deficient dipolarophiles such as fluorinated thioamides,[7d] and fluorinated enones. It is also worth noting that the presented protocol nicely supplements previously reported methods for the synthesis of rarely reported bis-trifluoromethylated pyrazoles, which are of interest in the context of not only pharmaceutical applications but also coordination chemistry.[1b,6d,18]

Scheme 4

Control Experiments Aimed at Aromatization of Pyrazole Ring

In summary, a novel protocol for the synthesis of two types of 3-trifluoromethylated pyrazoles, by using 5-acylpyrazolines as common precursors for highly selective, solvent-dependent oxidative aromatization with MnO2, was elaborated and examined in a series of experiments. Starting pyrazolines are readily available via fully regio- and diastereoselective (3 + 2)-cycloaddition reactions starting with corresponding chalcones and hydrazonoyl bromides applied as precursors of the in situ generated fluorinated nitrile imines, derived from trifluoroacetonitrile. The reported method is scalable and characterized by a wide tolerance of functional groups. For all these reasons it can be recommended for preparation of polysubstituted 3-trifluoromethylpyrazoles which can be of potential interest, e.g. for medicinal chemistry, crop protection industry, and materials chemistry. The presented work demonstrates once more the utility of 1,3-dipolar cycloaddition reactions (the Huisgen reaction[19]) in method development for synthesis of trifluoromethylated heterocycles.[20]