Iron-catalyzed trifluoromethylation of vinylcyclopropanes: facile synthesis of CF₃–containing dihydronaphthalene derivatives

Abstract

An efficient Fe(II)-catalyzed trifluoromethylation of vinylcyclopropanes was successfully developed. A series of CF₃-containing dihydronaphthalene derivatives were prepared in moderate to high yields (up to 96%) under mild reaction conditions using the Togni reagent as the CF₃ source.

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Introduction

Molecules bearing trifluoromethyl group(s), with remarkable biological activity, high hydrophobicity and metabolic stability, have been widely applied in the pharmaceutical and agrochemical industries.¹ Thus, during the past few decades, great effort has been devoted to the development of broadly applicable methods for constructing C–CF₃ bonds.² Among the transition metal catalysts, copper^3,4 and palladium⁵ complexes have been shown to be quite efficient for the construction of the C–CF₃ bond. In sharp contrast, iron, which is a widely abundant and environmentally benign transition metal, remains less explored in this area and only a few examples have been reported.⁶ After Yamakawa^6a in 2008 first reported an iron catalyzed trifluoromethylation of uracil, Gillaizeau^6b developed an iron catalyzed trifluoromethylation of enamides. Notably, Buchwald's group^6c achieved a significant breakthrough by using FeCl₂ as the catalyst to realize the trifluoromethylation of potassium vinyltrifluoroborates. Moreover, the groups of Plietker,^6d Sodeoka^6e and Shi^6f demonstrated that iron salts are capable of catalyzing the trifluoromethylation of carbonyl compounds, alkenes and alkylidenecyclopropanes to generate the corresponding trifluoromethylated products. Thus, in terms of sustainability, the discovery and development of iron catalysts for trifluoromethylation are still highly required.

Dihydronaphthalenes represent an important type of structural motif in many biologically active molecules and useful building blocks in organic synthesis.⁷ Consequently, many strategies have been developed for their synthesis.⁸ However, incorporation of the CF₃ group into dihydronaphthalenes has rarely been reported. In 2014, Fu⁹ and Xiao¹⁰ developed copper-catalyzed trifluoromethylation of internal alkynes to generate CF₃-containing dihydronaphthalenes, respectively (Scheme 1, eqn (a)). Very recently, Shi reported copper-catalyzed trifluoromethylation of methylenecyclopropanes resulting in CF₃-substituted dihydronaphthalenes¹¹ (Scheme 1, eqn (b)). Herein, we report the iron catalyzed trifluoromethylation of vinyl cyclopropanes, which includes the radical initiated ring opening and the subsequent intramolecular cyclization, to generate CF₃-containing dihydronaphthalenes with moderate to good yields under mild conditions.

Scheme 1 Comparison of various methods for the synthesis of CF₃-containing dihydronaphthalenes.

Results and discussion

At the outset, we chose the reaction of vinyl cyclopropane 1a catalyzed by CuCl as the model reaction to investigate different kinds of CF₃ reagents and found Togni's reagent 2a ¹² to be the most suitable CF₃ source to obtain the desired product 3a with 71% yield (Table 1, entries 1–3). It should be noted that FeCl₂ gave the product in higher yield and in a considerably shorter reaction time compared with the Cu catalyst (entry 1 vs. 4). To avoid the interference of the Lewis acid character of FeCl₂, other Lewis acids such as AlCl₃, Sc(OTf)₃, ZnCl₂ and CaCl₂ were tested to give no conversion (entries 5–8). Next, solvent screening showed that DCE, CH₂Cl₂ and CHCl₃ were suitable for this reaction (entries 4 and 9–14), and CH₂Cl₂ was identified as the best choice to give 82% yield at 40 °C only in 10 minutes. A comparable result (84% yield in 10 minutes) was obtained in the presence of ultrapure FeCl₂, thus suggesting that the catalyst system is iron based (entry 15).^13,6b,c However, performing the reaction at room temperature led to a prolonged reaction time to 2.5 hours (entry 16). Reducing the catalyst loading to 5 mol% resulted in a lower yield (entry 17). Based on these optimization experiments, entry 13 was identified as the optimal conditions for the substrate scope investigations.

Table 1 Optimization of reaction conditions^a

Entry	Cat.	Solvent	Temp. (°C)	Time	Yield^b (%)
a Reaction conditions: 1a (0.30 mmol), 2a (1.3 equiv), catalyst (10 mol%), and solvent (2 mL) were used. b The yields of isolated products. c 2a was replaced by 2b. d 2a was replaced by 2c. e No reaction. f Ultrapure FeCl2 (99.998% based on trace metals, Sigma-Aldrich) was used. g 5 mol% of FeCl2 was used.
1	CuCl	DCE	60	75 min	71
2^c	CuCl	DCE	60	15 h	63
3^d	CuCl	DCE	60	15 h	NR^e
4	FeCl2	DCE	60	10 min	80
5	AlCl3	DCE	60	24 h	NR^e
6	Sc(OTf)3	DCE	60	24 h	NR^e
7	ZnCl2	DCE	60	24 h	NR^e
8	CaCl2	DCE	60	24 h	NR^e
9	FeCl2	DMSO	60	24 h	10
10	FeCl2	THF	60	24 h	60
11	FeCl2	MeCN	60	24 h	NR^e
12	FeCl2	Toluene	60	24 h	40
13	FeCl2	DCM	40	10 min	82
14	FeCl2	CHCl3	40	40 min	80
15^f	FeCl2	DCM	40	10 min	84
16	FeCl2	DCM	25	2.5 h	79
17^g	FeCl2	DCM	40	12 h	50

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The scope and limitations of substrates were investigated as shown in Table 2. The substituent effect on the 2-phenyl ring (R¹) was firstly probed. Both electron-withdrawing and -donating groups at the para-position of the phenyl ring led to the desired products (3b–3f) in good yields (82%–89%). For substrate 1g bearing a methyl group at the meta-position, the desired product 3g could be obtained as the sole product in 93% yield. 1,2-Dihydroanthracene derivative 3h was also obtained in 92% yield. We then screened the general scope of R² at the cyclopropane ring. As for substrates 1i–1n, in which the R² groups are a range of para-substituted phenyl groups, the corresponding products 3i–3n were formed in high yields (92–96%). The molecular structure of 3l, established by X-ray diffraction, confirmed the ring opening of the cyclopropane unit, which was carried out between C3 and C5 regioselectively (Fig. 1). Though the reason for the high regioselectivity of the cyclopropane ring opening in this system is unclear, we proposed that FeCl₂ may also coordinate with the two ester groups to assist C3–C5 bond breaking.¹⁴ Notably, 2-naphthyl (3o), 2-thienyl (3p) and isopropyl (3q) groups were also tested in the reaction and afforded the desired products in high yields. However, substrate 1r (R² = H) was only converted into the corresponding product 3r in a relatively low yield (17%). In addition, we also investigated the influence of the ester substituent (R³). Upon going from 3s to 3t, the bulkier substituent was found to reduce the reactivity, with the tert-butyl ester being converted to the product 3u in 67% yield. Remarkably, the reaction could be scaled up to gram quantities smoothly and provided 3a in 90% yield.

Fig. 1 Molecular structure of product 3l.

Table 2 Substrate scope of 1

a 3.30 mmol of substrate 1a was used.

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To highlight the synthetic utility of this method, we undertook further transformations of the resulting dihydronaphthalenes (Scheme 2). The C=C bond can easily undergo hydrogenation¹⁵ to form the corresponding tetrahydronaphthalene products 4 with the cis configuration (determination by using the NOESY spectrum, see the ESI†) in excellent yields. Successive decarboxylation and autoxidation¹⁶ of 3a gave the naphthalene 5 in 75% yield.

Scheme 2 Further transformations of the products 3.

Based on the above results and previous related reports,^6b,11,17 a plausible mechanism for this catalytic reaction is proposed in Scheme 3. In the initial step, the Togni reagent 2a reacts with FeCl₂ to generate the CF₃ radical, followed by a reaction with substrate 1a to give the radical intermediate A, which undergoes a ring-opening process to form the radical intermediate B. Subsequently, there are two possible ways for the formation of cationic intermediate E from B. In path a, radical B undergoes radical addition to obtain intermediate C, which would be oxidized by Fe(III) to afford cation E. An alternative reaction pathway involving the formation of cation D through single-electron oxidation from Fe(III) species, followed by a subsequent Friedel–Crafts reaction also resulting in intermediate E, could not be excluded at the present stage (path b). Finally, E could further undergo deprotonation to furnish the desired product 3a.

Scheme 3 Plausible reaction mechanism.

Conclusions

In conclusion, we have successfully developed an efficient Fe-catalyzed trifluoromethylation of vinylcyclopropanes and subsequent intramolecular cyclization for the direct synthesis of CF₃-containing dihydronaphthalenes under mild conditions. The reaction can be readily scaled up to gram amounts and the products 3 can be converted into the corresponding tetranaphthalenes or naphthalene by further hydrogenation or decarboxylation/oxidation, respectively. Further studies on mechanistic investigations and the applications of this protocol are ongoing in our group.

Acknowledgements

Q.-H. Deng is grateful for the generous financial support from the Program of the Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, the National Natural Science Foundation of China (no. 21402119), and the Shanghai Rising-Star Program (no. 16QA1403100). F. Liu is grateful for the financial support from the National Natural Science Foundation of China (no. 21302134), the Natural Science Foundation of Jiangsu (no. BK20130338), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, characterization data, NOESY spectra, NMR spectra for new compounds, and CIF file giving crystallographic data for compound 3l. CCDC 1474908. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00166a

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