Synthesis of 5-(Trifluoromethyl)pyrazolines by Formal [4 + 1

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Synthesis of 5‑(Trifluoromethyl)pyrazolines by Formal [4 + 1]Annulation of Fluorinated Sulfur Ylides and Azoalkenes Zhiyong Wang,† Yanzhou Yang,† Fang Gao,† Zhiyong Wang,*,† Qian Luo,‡ and Ling Fang*,‡ †

School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, China College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China

‡

S Supporting Information *

ABSTRACT: In situ formed 1,2-diaza-1,3-dienes were used in formal [4 + 1]-annulation reactions with fluorinated sulfur ylides. This protocol provides a novel and efficient method for the synthesis of 5-(trifluoromethyl)pyrazolines in moderate to excellent yields.

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Scheme 1. Approaches to Synthesis of TrifluoromethylSubstituted Pyrazoline Derivatives

rifluoromethylated aromatic and heterocyclic compounds are extensively used in the fields of pharmaceutical, agrochemical, and material sciences.1,2 As important members of these families, trifluoromethyl-substituted pyrazolines have attracted special interest because of their myriad biological activities (Figure 1).3 Conventionally, functionalized trifluoromethyl-substituted pyrazolines have been obtained from the corresponding 1,1,1-trifluoro-α-enones by means of condensation reactions with the substituted hydrazines (Scheme 1, eq 1).4 Recently, [3 + 2] dipolar cycloaddition between in situ generated trifluorodiazoethane and electron-deficient alkenes (Scheme 1, eq 2) or electron-deficient allenes (Scheme 1, eq 3) has been established by Mykhailiuk5 and Ma,6 respectively, as an alternative strategy to access biologically interesting 5(trifluoromethyl)pyrazolines. However, these protocols are somewhat limited due to poor regioselectivity, narrow substrate scope, and potential hazardousness. Therefore, it is highly desirable to develop mild protocols to access trifluoromethylsubstituted pyrazoline derivatives. Currently, the rapid and reliable synthetic approaches that enable straightforward syntheses of several different heterocyclic frameworks from easily available precursors are especially preferable in the process of drug discovery. Recently, azoalkenes (1,2-diaza-1,3-dienes), which are generated in situ from α-halogeno ketohydrazones, have been widely employed as powerful and versatile four-unit intermediates in kinds of annulations.7 This strategy has led to new synthetic methods for a variety of valuable nitrogen-containing heterocycles, such as pyrazole8 and pyrazoline9 derivatives via [4 + 1]-annulations

Scheme 2. Proposed [4 + 1]-Annulation of in Situ Generated Fluorinated Sulfur Ylide and Azoalkenes

as well as functionalized tetrahydropyridazines9c,10a−g and 1,2,3,4-tetrazines10f by means of [4 + 2]-annulations. Biological seven-membered N-heterocycles could be even accessed by [4 + 3]-annulations.8c,11 Meanwhile, sulfur ylides are a well-known class of C1 synthons in the cascade annulation process for synthesis of structurally diverse carbo- and heterocycles.12 However, fluorinated sulfur ylides have been minimally investigated.13 Very recently, Xiao13b−d and co-workers found that trifluoroethyl diphenylsulfonium triflate [Ph2S+CH2CF3−OTf]14 was elegantly used as a versatile and convenient trifluoroethylidenesulfur ylide reagent for Johnson− Received: December 6, 2017

Figure 1. Biologically active trifluoromethylated pyrazolines. © XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.7b03811 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 3. Substrate Scopea,b

entry

base

solvent

3a, yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

KF CsF TBAF Na2CO3 K2CO3 Cs2CO3 K3PO4 DBU Et3N K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

THF THF THF THF THF THF THF THF THF CH2Cl2 CH3CN toluene DMF THF THF THF

15 72 trace 0 86 66 68 trace 0 70 80 trace 18 90c 96d 93d,e

a

Unless noted otherwise, reactions were conducted with 1a (0.15 mmol), 2a (0.30 mmol), base (0.45 mmol), and 4 Å MS (0.4 g) in solvent (1.5 mL) at rt under Ar. bIsolated yield based on 1a. cTHF (3 mL). dTHF (6 mL). e4.0 equiv of K2CO3 was used.

Corey−Chaykovsky trifluoroethylidenation reactions. Inspired by the aforementioned works as well as our efforts in the synthesis of biologically interesting heterocycles,15 we surmised that a novel [4 + 1]-annulation 16 reaction could be accomplished between trifluoroethylidenesulfur ylide and azoalkenes, which can open a direct entry for the synthesis of biologically important 5-(trifluoromethyl)pyrazoline derivatives as outlined in Scheme 2. Still, a few challenges had to be encountered, such as (1) both reactants are unstable and highly reactive, their generation and use usually proceeds by in situ transformation of the corresponding precursors; (2) reaction conditions which can control the formation of the intermediates and the following annulation process need to be found; and (3) dimerization10a,f of the azoalkenes must be addressed. With this in mind, we attempted the reaction of α-bromo Nacetyl hydrazone 1a with trifluoroethyl diphenylsulfonium triflate 2a in tetrahydrofuran at room temperature with various bases. Preliminary screening showed that the base has a remarkable effect on the reaction. For instance, the reaction with CsF as the base gave the desired 5-(trifluoromethyl)pyrazoline 3a in 72% yield (Table 1, entry 2). It was found that the reaction proceeded efficiently when K2CO3 was employed as base, leading to the desired product 3a in better yield (Table 1, entry 5). However, the organic bases seemed to be inefficient in this transformation (Table 1, entries 8 and 9). Subsequently, different solvents were then explored (Table 1, entries 10−13), and tetrahydrofuran was the best choice. Notably, a slightly higher yield was obtained with the lower substrate concentrations (Table 1, entries 14 and 15). An increase of the amount of the base used to 4.0 equiv did not lead to a better yield (Table 1, entry 16).

a

Unless noted otherwise, reactions were conducted with 1 (0.15 mmol), 2a (0.30 mmol), K2CO3 (0.45 mmol), and 4 Å MS (0.4 g) in THF (6.0 mL) at rt under Ar. bIsolated yield based on 1. cα-Chloro hydrazones were used. d(2,2-Difluoroethyl)diphenylsulfonium triflate [Ph2S+CH2CF2H−OTf] 2b was used in place of 2a.

After the optimal conditions were established (Table 1, entry 15; 3.0 equiv K2CO3 in 6 mL of THF at room temperature), we subsequently assessed the scope of the method by varying the α-halo hydrazone component and evaluating isolated yields (Scheme 3). As shown in Scheme 3, we were pleased to find that both α-chloro and α-bromo hydrazones 1 proved to be good azoalkene precursors in this annulation reaction. A variety B

DOI: 10.1021/acs.orglett.7b03811 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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Scheme 4. Gram-Scale Experiment

Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Zhiyong Wang: 0000-0002-4665-4339 Notes

The authors declare no competing financial interest.

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of α-halo hydrazones bearing electron-withdrawing and -donating substituents at the ortho, meta, and para positions on the benzene ring produced the corresponding 5(trifluoromethyl)pyrazolines 3 in moderate to excellent yields upon reaction with ylide 2a (Scheme 3, 3a−n). For instance, sterically bulky 2-fluoro-substituted hydrazone 1f worked well in this annulation, and the corresponding product 3f was obtained in moderate yield (65%). The more electron-deficient nitro-substituted analogue 1i is also compatible with the reaction conditions, leading to 3i in 92% isolated yield. In addition, 2-naphthyl-substituted hydrazone 1o turned out to be a good substrate to undergo the desired reaction with 96% yield (Scheme 3, 3o). Remarkably, this method was also amenable to an alkyl substituted hydrazone 1p. Probably due to the diminished stability of the in situ generated azoalkene, the desired product 3p was obtained in only acceptable yield. It is noteworthy that cyclic hydrazone 1q was proven to be a suitable substrate, affording the biologically interesting polycyclic adduct 3q in moderate yield. Moreover, this indicates that the reactivity of the annulation is significantly influenced by the N-protecting group on the hydrazone: 3r (N-Boc) and 3s (N-Bz) showed lower isolated yields, while N-tosyl hydrazone 1t gave no product under these optimal conditions. Further screening revealed that (2,2-difluoroethyl)diphenylsulfonium triflate [Ph2S+CH2CF2H−OTf] 2b is not a suitable fluorinated sulfur ylide precursor for this reaction at the current stage, probably due to the instability of the corresponding ylide13b (Scheme 3, 3u). To show the synthetic potential of our present methodology, a gram-scale reaction using the current [4 + 1]-annulation worked well without affecting the efficiency of the reaction (Scheme 4). In summary, a new method for the synthesis of 5(trifluoromethyl)pyrazoline derivatives via catalyst-free [4 + 1]-annulation of α-halo hydrazones with trifluoroethyldiphenylsulfonium triflate is practical and reliable. The transformation involves in situ generation of the reactive 1,2-diaza1,3-dienes under mild conditions, and trapping with in situ formed unstable trifluoroethylidenesulfur ylide. Our findings not only provide an excellent alternative to 5-(trifluoromethyl)pyrazoline derivatives but also lay a foundation for harnessing reactive trifluoroethylidenesulfur ylide as a useful synthetic intermediate.

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ACKNOWLEDGMENTS Financial support from National Natural Science Foundation of China (Nos. 21602025 and 21302236), the Foundation of Chongqing Science & Technology Commission (cstc2015jcyjA10086), and the Fundamental Research Funds for the Central Universities (CDJRC11220001, 106112016CDJXY220004) is gratefully acknowledged.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03811. Experimental procedures and compound characterization data (PDF) C

DOI: 10.1021/acs.orglett.7b03811 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.7b03811 Org. Lett. XXXX, XXX, XXX−XXX